NY 290 begins at an intersection with US 11 in the shadows of I-81 and I-690 in downtown Syracuse. NY 290 proceeds northeast along James Street, a four-lane commercial street through downtown Syracuse, crossing through the Near Northeast neighborhood. Passing numerous apartment buildings and residential complexes, the route continues past multiple commercial businesses before crossing into the Sedgwick neighborhood. NY 290 continues along James Street, now a four-lane residential street in a less dense section of Syracuse. Crossing Teall Street, the southern continuation of County Route 228, the route enters the Eastwood neighborhood of Syracuse. In Eastwood, NY 290 continues northeast along James Street until reaching Shotwell Park, where it junctions with Grant Boulevard. At this junction, NY 290 turns eastward along James Street, becoming a two-lane commercial street. Several blocks to the east of Grant, NY 290 reaches a junction with NY 598. Continuing through Eastwood, the route expands to four lanes near the localwater tower and crosses into the town of De Witt, where it junctions with NY 635 above railroad tracks. NY 290 continues eastward through De Witt, becoming a four-lane boulevard through the town, reaching a fork with West Manlius Street, where James Street continues east as CR 53A and NY 290 turns southeast on West Manlius. Back to two lanes, NY 290 proceeds southeast along West Manlius Street, a residential street through De Witt before crossing into the village of East Syracuse. At the junction with Burnet Street, NY 290 enters the center of East Syracuse, becoming a two-lane commercial street, changing to East Manlius Street at North Center Street. Two blocks east of this junction, NY 290 reaches a junction with Bridge Street, where East Manlius continues towards CR 77, while NY 290 turns southeast on Bridge. Crossing over tracks used by CSX Transportation by its Mohawk Subdivision, NY 290 reaches a junction with Bridge Street and Manlius Center Road, where NY 290 turns northeast along Manlius Center. Now a six-lane arterial, NY 290 proceeds northeast through East Syracuse, turning east as it bypasses the Walmart Connection Center. Crossing back into the town of De Witt, the route reduces to two lanes, crossing under the lanes of I-481. The route becomes a two-lane commercial street through De Witt, soon crossing into the town of Manlius. Through Manlius, NY 290 does not change from a two-lane commercial roadway, turning southeast near Fremont Road. Becoming a residential road, the route reaches a junction with the northern terminus of North Burdick Street. Near Sunset Drive, the route turns eastward once again, running along the northern edge of The Links at Erie Village, turning southeast again at Clemons Road. NY 290 crosses over Limestone Creek as it runs southeast through Manlius. Passing a junction with Minoa Road, the route crosses over an old alignment of the Erie Canal and reaches a junction with the northern terminus of NY 257. At this junction, NY 290 turns northeast as Green Lakes Road, paralleling the former Erie Canal through the town of Manlius. Passing Green Lakes State Park, the route passes the main entrance gate as it bends eastward along the canalway. At the junction with Pierson Road, the route leaves Green Lakes State Park and continues eastward away from the old canal. Now a two-lane farm road, NY 290 reaches a junction with the southern terminus of Kirkville Road North. Just east of this junction, NY 290 reaches a junction with Kinderhook Road, where it turns southeast along Green Lakes. Now a two-lane residential/rural roadway, NY 290 continues southeast into the hamlet of Mycenae, where it reaches a junction with NY 5. This junction marks the eastern terminus of NY 290, less than from the Madison County line.
