Macquarie Park was part of the suburb of North Ryde until it was gazetted as a suburb in its own right on 5 February 1999, and many businesses still use North Ryde as the address. Both suburbs share the 2113 postcode but Macquarie University, which is located at the northern part of the suburb, has its own postcode of 2109.

The area between Parramatta and Lane Cove Rivers was originally known by its Aboriginal name Wallumatta. The Aboriginal name survives in a local park, the Wallumatta Nature Reserve, located at the corner of Twin and Cressy Roads, North Ryde.

Macquarie Park is named for Governor Lachlan Macquarie (1762–1824), a British military officer and colonial administrator who served as the Governor of New South Wales from 1810 to 1821. The area that is now Macquarie Park was part of the suburb of North Ryde from the late 19th century. The area was once filled with market gardens, poultry farms and vast tracts of bushland, with many beautiful picnic spots and waterfalls.

The mid-1960s saw the establishment of Macquarie University and the 'Macquarie Park Employment Area' which saw the rezoning of 'Green Belt' bushland to allow for industrial activities. The initial concept for Macquarie Park was based on the idea of a similar hi-tech industrial area surrounding Stanford University in Palo Alto, California, the goal being to provide for the interaction between industries and the university.

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