I grew up in Western NY, south of Buffalo, and know the roads pretty well inland from Lake Erie.
Here's one possibility: From Titusville, Spring Creek Rd (which I don't know at all) to Oil Creek Rd to Messinger Rd, cross US6, to Kidder Rd, to PA958 north, to PA957 east, through Sugar Grove, to Jamestown Street, which (through a couple of name changes) takes you to Jamestown NY.
Seek NY394 east. That's the old NY17 before they made an expressway out of it, so is adapted to 1970-era heavy traffic. Think wide and flat, nice shoulders, and most traffic is local.
Just past East Randolph, peel left onto NY242. Stay on that to Ashford Jct, where you'll peel left onto NY240. You'll be on 240 a llllllooooonnnnnnggggg time. If you want to go to the Falls, stay on it allllll the way to the end. Just know that you'll be on some busy streets as you get into metro Buffalo, but unlike Pittsburgh, everything is fairly wide (so they have someplace to plow the snow onto), and also goes in straight lines.
Anyway, there's no avoiding traffic, as one thing Western NY does not have is trails along streams. From time to time there's a decent road along a stream, so here's how I get you to N.F. from the north end of 240 (a.k.a. Harlem and Sheridan): L Sheridan, R Sweet Home Rd, L South Ellicott Creek Rd, R Colvin Blvd, L Moon Walk (yes, really), which becomes Fillmore, jiggle L-R at Niagara St onto Delaware, becomes Main, R Tremont, L Oliver, ...
...then things get dicey. There are only two roads that go west, and they're both super-busy. I'd L at Ward Rd and go to river's edge, where there's a park. When you feel up to it, leave the park, turn L and duke it out on NY384 until L on 1st Street takes you over to Goat Island, and you can't get much closer to the falls than that.
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I grew up in West Falls, along 240, so can tell you that you have a long, gentle downhill for about 10 miles from a bit beyond Springville (which you just miss but might be worth going a mile out of your way if you need supplies) to West Falls, then again a gentle slope from about Orchard Park into the eastern suburbs of Bflo. Most of the eastern and northern areas of metro Bflo are close to flat.