IIRC, I read in one or more of the Hendrix biographies (cant’ remember which - it’s been a while) that he first learned to play with the guitar still strung for a righty, a la Albert King, then only started restringing the guitars when he started playing Strats, since the upper cutaway allowed him to reach the higher notes easier - when playing on an upside-down Tele or LP, why even bother restringing when you can’t reach a third of the guitar’s range easily for lack of cutaway?
In fact, it’s been posited that without the Strat, he wouldn’t have really developed into the player he did. The Gibson guitars like the SG and Vee - while they had easy access to the upper registers on both sides of the neck - had an offset, fixed bridge that didn’t allow him to reset the intonation for in-tune lefty playing, plus the trem units available weren’t that great (mostly Bigsby variants that went out of tune when you winked at them). Ditto for the DanElectro Longhorn, and other more esoteric models at the time. The Strat, with a relatively stable tremolo, long string saddle screws allowing decent variation of string length, and angled cable jack, was almost made to be played the way Hendrix wanted to play.
As a lefty myself, I’ve only had two guitars that were actually left-handed (an LP copy and an Epi Joe Pass jazzbox), the rest were an eclectic combination of righty-and-lefty strung right-handed guitars - currently I play a restrung Tele - however, playing with the low E on the bottom certainly lets you do some rythm things nearly impossible when strung correctly.
Interestingly, I think surf guitar great Dick Dale plays right handed, but strings his guitars lefty. And Stevie Ray’s main guitar, while right-handed, had a lefty tremolo. . . illustrating that there can be different advantages with an opposite-hand setup.