Millersburg is located in northwestern Dauphin County on the east bank of the Susquehanna River at 40°32′30″N 76°57′26″W / 40.54167°N 76.95722°W / 40.54167; -76.95722 (40.541676, -76.957283).Wiconisco Creek enters the Susquehanna at the southern edge of the borough. According to the United States Census Bureau, Millersburg has a total area of 0.76 square miles (1.97 km²), all of it land.

Millersburg is the southwestern terminus of U.S. Route 209, which leads northeast 44 miles (71 km) to Pottsville and 211 miles (340 km) to its northeastern terminus north of Kingston, New York. Pennsylvania Route 147 passes through the center of Millersburg as Market Street, leading north (upriver) 29 miles (47 km) to Sunbury and south (downriver) 13 miles (21 km) to U.S. Route 22 near Duncannon. The Millersburg Ferry leads west across the Susquehanna to Buffalo Township in Perry County, allowing a connection to U.S. Routes 11 and 15.