Midway through the town of Rush, NY 251 widens from two to four lanes and meets I-390 at exit 11. Just east of the freeway, NY 251 intersects NY 15, which is also served by exit 11 by way of a pair of short collector/distributor roads paralleling I-390 from NY 251 to NY 15. Past NY 15, the route reverts to a two-lane highway and veers southeast to parallel Honeoye Creek into the hamlet of Rush. Here, the route passes through a more populated area as it intersects NY 15A in the center of the community, at which point it becomes Rush–Mendon Road. NY 251 continues to follow Honeoye Creek through progressively less developed areas and into the town of Mendon, where the creek curves southward toward Honeoye Falls at Rochester Junction. The highway, however, turns northeastward to meet NY 65 at a roundabout. The northeasterly routing of NY 251 continues to Mendon Center, a small hamlet near the southern tip of Mendon Ponds Park, where it turns eastward once more.