Best route from north FL to north side of SMNP?

Depends on how much time you want to spend on I-75, and do you mind going thru Atlanta? Fastest would be US-319 to Tifton, I-75 up from there. US-27 up to Columbus, I-185/85/75 works good also. We reverse this going south to Quincy FL every year. US-27 up to Rome GA will miss Atlanta. There if you want you can pick up US-411 and take it To Maryville TN. Or GA-53 to I-75 at Calhoun GA.