During the 1950s and early 1960s, the portion of the Eastern Expressway from what is now the Can of Worms east to Bushnell's Basin was originally designated as part of NY 96.

[citation needed] Between the Mount Read Boulevard interchange at exit 10 and the Genesee River, I-490 is referred to as the "Western Gateway".

This section, which saw major decorative and structural improvements in the late 2000s,[7] travels due east through heavily residential neighborhoods before turning to the southeast near Innovative Field and a junction with the Inner Loop at exit 13.

[10] At this point, the former Erie Canal route (now part of I-590) curves southward[8] while I-490 continues eastward into the eastern suburbs of Rochester.

Between exits 21 and 24, I-490 parallels the CSX Transportation-owned Rochester Subdivision rail line, intersecting NY 441, a four-lane divided highway in the process.

The freeway meets NY 96 twice in Perinton and a third time in the Ontario County town of Victor, where I-490 passes along the western fringe of Eastview Mall.

[citation needed] The portion of I-490 from exit 15 southeast to the Can of Worms follows the original path of the Erie Canal through the city of Rochester.

As ridership on the line declined in the 1940s and early 1950s, the city elected to shut the subway down in 1956 and use the right-of-way for a new highway connecting the Inner Loop to the recently completed New York State Thruway south of Rochester.

[20] The last two gaps in the freeway—from Mount Read Boulevard east to the Inner Loop in Rochester and from Bushnell's Basin southeast to the thruway in Pittsford and Victor—were filled in the early 1970s.

The plan called for the demolition of a number of RIT buildings and would have resulted in splitting the campus into two halves separated by the new freeway.