What is the best interstate route from Knoxville TN to Buffalo NY?

The best interstate route from Knoxville, TN, to Buffalo, NY, is to take I-75 North to I-40 East, then merge onto I-81 North. Continue on I-81 until you reach I-86 East, which will lead you toward Buffalo. This route offers a balance of efficiency and scenic views, covering approximately 600 miles.