The first training session for the season took place on 9 June 2016 at APOEL's training centre. On 18 June 2016 the team flew to Gniewino in Poland to perform the main stage of their pre-season training and returned to Cyprus on 30 June 2016. During the pre-season training stage in Poland, APOEL played four friendly matches, drawing 1–1 with FK Atlantas, losing 1–2 to Lechia Gdańsk, winning 1–0 against FK Partizan and drawing 1–1 with Viitorul Constanța. After their return to Cyprus, APOEL played one more friendly match, beating Greek side PAS Giannina 2–1 at Dasaki Stadium on 5 July 2016.

On 10 August 2016, APOEL lost 1–2 to Apollon Limassol at GSP Stadium in the Super cup final. Apollon took the lead after 39 minutes when a cross from the left went past a sea of bodies and was fortuitously knocked into the net by Anton Maglica, and Arkadiusz Piech added a second with an acrobatic volley from close range eleven minutes before the end. APOEL's consolation goal came in the final minute of added time when a shot from Georgios Efrem deflected off Nuno Lopes' back to turn the ball past his own keeper.

APOEL's opening Cypriot First Division match against Anorthosis was originally scheduled on 20 August 2016, but was postponed and rescheduled to a later date because of APOEL's UEFA Champions League play-off matches against FC Copenhagen. On 28 August 2016, APOEL opened their competitive season with a comfortable 3–0 win at GSP Stadium against Ermis Aradippou. Nuno Morais opened the scoring five minutes before the break, before Giannis Gianniotas and Georgios Efrem complete the scoring with two goals in the last ten minutes of the match. On 10 September 2016, APOEL registered their second straight league win after thrashing Nea Salamina 4–0 at Ammochostos Stadium. Pieros Sotiriou gave his team the lead just before the half hour mark and doubled his tally eleven minutes from the end. Belgian striker Igor de Camargo got off the mark with a fine goal before laying off for Georgios Efrem to score into stoppage time. On 18 September 2016, APOEL maintained their perfect start by beating Anagennisi Deryneia 2–0 at home, following second half goals from Belgian striker Igor de Camargo and a strike from distance from Brazilian winger Vander. On 21 September 2016, in the first matchweek game which was postponed and rescheduled, APOEL dropped their first points of the season after being held to a goalless draw by Anorthosis at Antonis Papadopoulos Stadium. On 25 September 2016, APOEL had no troubles beating Aris Limassol 3–0 at Tsirion Stadium, thanks to a Giannis Gianniotas' goal just before the half-time and two second-half goals by Vinícius and Giorgos Merkis. On 2 October 2016, APOEL got a hard-earned 2–0 win over Doxa Katokopias at GSP Stadium thanks to two late goals from Georgios Efrem and Giannis Gianniotas. On 15 October 2016, APOEL beat AEZ Zakakiou 4–1 at Pafiako Stadium, to register their sixth win in the first seven matches. Facundo Bertoglio and Pieros Sotiriou scored for APOEL in the first half, while Georgios Efrem scored twice in the second half to make it 4–0. Konstantinos Pangalos scored AEZ's consolation goal in the last minute of the match, marking APOEL's first conceded league goal of the season. On 24 October 2016, APOEL claimed a hard-fought 2–0 win over Ethnikos Achna at GSP Stadium thanks to two second half goals by Pieros Sotiriou. On 29 October 2016, in the top of the table clash, APOEL and AEK Larnaca shared the spoils in a 1–1 draw at the new AEK Arena at Larnaca. APOEL opened the scoring on the hour mark after Vinícius took advantage of AEK's defenders mistake to slot the ball into an empty net. AEK equalized just six minutes later after Daniel Mojsov's back-post header hit André Alves' head before finding the net. These were the first points dropped by AEK so far this season after eight straight wins, but the result still kept them at the top, two points ahead of APOEL. On 6 November 2016, two days before their 90th birthday anniversary, APOEL beat Karmiotisssa 4–1 at home, and remained in the second place, three points behind AEK Larnaca. Pieros Sotiriou opened the scoring for APOEL after 13 minutes, but David Poljanec got an equalizer for Karmiotissa in the 36th minute. Pieros Sotiriou netted his second ten minutes after the restart to give again his team the lead, while APOEL managed to score two more goals in the last 15 minutes through Efstathios Aloneftis and Renan Bressan. On 19 November 2016, APOEL suffered their first league defeat of the season, losing 0–1 away to AEL Limassol thanks to an 86th minute penalty by Mikel Arruabarrena. On 28 November 2016, APOEL drew 1–1 at home against Apollon Limassol and dropped to third place of the league table, four points behind leaders AEK Larnaca. Alex da Silva gave Apollon the lead midway through the second half after converting a penalty, but Facundo Bertoglio scored a last-gasp equalizer with a close range diving header to rescue a point for APOEL. On 3 December 2016, APOEL ended the first round of the regular season with a resounding 4–1 away win over their arch-rivals Omonia and moved to within two points of the top of the table. APOEL took the lead in the 18th minute with a penalty converted by Georgios Efrem, while Omonia's defender Carlitos was sent off in the same incident. With the numerical advantage in their favour, APOEL scored two more goals before the half time through Pieros Sotiriou. Renato Margaça managed to pull one back for Omonia early in the second half, but Vinícius wrapped up the goals for the day with APOEL's fourth in the 67th minute. On 12 December 2016, APOEL beat Anorthosis 2–1 at home and joined the leading duo AEK and AEL on 33 points at the top of the table. Igor de Camargo put APOEL ahead four minutes before the halftime, and Iñaki Astiz added a second in the 89th minute. Anorthosis managed only to pull a goal back a minute later through Esmaël Gonçalves. On 17 December 2016, APOEL drew 1–1 away against Ermis Aradippou and dropped to third place of the league table, despite of completely outplaying their opponents counting 25 attempts on goal as opposed to just two from Ermis. Edward Mashinya gave his teams the lead in the ninth minute and APOEL equalized thanks to a Facundo Bertoglio's header twelve minutes from the end. On 21 December 2016, in the last match of the year, Igor de Camargo's 47th-minute header was enough for APOEL to beat Nea Salamina 1–0 at home and move up to second place, two points behind AEK Larnaca. On 3 January 2017, APOEL moved to the top of the table along with AEL Limassol after a comfortable 4–2 away win against bottom placed Anagennisi Deryneia. Efstathios Aloneftis opened the scoring for APOEL in the 10th minute and seven minutes later Vinícius doubled his teams' lead with a close range header. Vinícius added a third on the hour mark, but twenty minutes from time, Deryneia scored twice in the space of 90 seconds with Wesllem and Rúben Brígido, before Giannis Gianniotas score APOEL's fourth two minutes later to seal the three points for his team. On 8 January 2017, APOEL thrashed Aris Limassol 5–0 at home to sit alone at the top of the standings for the first time in the season. Pieros Sotiriou scored the first hat-trick of his career with less than an hour played, while Georgios Efrem completed APOEL's easy victory with a brace. On 14 January 2017, APOEL beat Doxa Katokopias 2–0 at Makario Stadium thanks to a first half goal from Igor de Camargo and a Pieros Sotiriou's header eleven minutes from time. On 22 January 2017, APOEL increased their lead at the top to three points after thrashing AEZ Zakakiou 7–0 at GSP Stadium. Early strikes from Cypriots Efstathios Aloneftis, Pieros Sotiriou, Giorgos Merkis, and braces from strikers David Barral (who made his debut) and Igor de Camargo ensured an emphatic win for the Cypriot champions. On 29 January 2017, APOEL moved five points clear at the top of the league standings after a 3–2 away win against Ethnikos Achna. Ethnikos took the lead through Ioannis Chadjivasilis after just 13 minutes, but Igor de Camargo equalized for visitors 10 minutes later. Defender Iñaki Astiz gave APOEL the lead in the 38th minute, while Giannis Gianniotas secured the win twelve minutes from time. Eduardo Pincelli managed just to pull one back for Ethnikos from the penalty spot in the fifth minute of the added time. On 5 February 2017, in the top of the table clash, APOEL were held to a 1–1 draw by AEK Larnaca at the GSP Stadium, allowing AEL and Apollon to move to within three and four points off the top. AEK's new signing Florian Taulemesse opened the scoring eight minutes before the break, and APOEL managed to equalize 15 minutes from the end through Pieros Sotiriou who took advantage of a lapse in the AEK defence and slid the ball past goalkeeper. On 5 February 2017, APOEL extended their lead at the top to five points following their narrow 1–0 away win over Karmiotissa and the failure of their closest rivals AEL and Apollon to defeat their opponents. With their Europa League tie against Athletic Bilbao at the back of their minds, APOEL managed to clinch the win thanks to a Facundo Bertoglio's goal in the 5th minute after an excellent combination with Efstathios Aloneftis. On 20 February 2017, APOEL beat AEL Limassol 3–0 at the GSP Stadium in the top-of-the-table clash and moved six points clear at the top. Despite of that coach Thomas Christiansen rested six players ahead of the crucial UEFA Europa League round of 32 match against Athletic Bilbao, APOEL got an easy and well deserved victory. Vinícius put APOEL ahead on 34 minutes with a close range header and Nuno Morais doubled the score after a dreadful Kevin Lafrance mistake in the 78th minute.Igor de Camargo scored the third in stoppage time from the penalty spot after being brought down by AEL goalkeeper. On 27 February 2017, APOEL lost 2–0 away to second placed Apollon Limassol following goals from Anton Maglica and João Pedro, and the gap between the two teams was reduced to just three points. On 4 March 2017, APOEL beat arch-rivals Omonia 2–1 at home and ended the regular season atop league standings, four points ahead of second placed AEK Larnaca. Two penalties converted by Pieros Sotiriou and David Barral in the last two minutes of the first half were enough to give APOEL a deserved win, while Matt Derbyshire scored the consolation goal for Omonia three minutes before the end.

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