We did that one time. That was enough, IMHO.
301 is, as SamR said, full of small towns and stoplights. Also, when we tried it last, the route was stamped on the
AAA info as a 'speed enforcement zone', which translates to 'speed trap'. Starke and Waldo used to be notorious for that, back in the pre-2000 days. We drove 301 down toward Gainesville, then got on 75 right after.
Yes, it is a nice enough drive, but with my radar detector going off for over 60% of the time we were on that road, I have to believe that it was indeed a speed trap area. The speed limit changed constantly along that road, which seemed to lend itself to getting a ticket.
As an alternative to 95 and 4, it works on the map. But the actual drivng of 301 was painfully slow, with freqent speed limit changes, police sitting on the side of the road often, and an enormous amount of traffic lights and small towns slowing things down.
You won't know for sure if it's for you until you try it. But for us, once was enough.
Either way you go, travel safely.