Define "most powerful" please.
Total foot-pounds for an average loading at the muzzle? At 100 yards? Largest caliber? Highest FPS at muzzle or some set distance? Heaviest bullet?
Do we include obsolete handguns, antiques? Just limit it to common commercial production within the 20th and 21st centuries? Can we include custom one of a kind pistols?
I guess the most fair answer would be total foot-pounds at the muzzle, open to any make or era. By that criteria, I'd guess it would be one of the .50 BMG pistols that have been produced, or that custom Thompson Contender chambered in .600 Nitro Express, where it flips over the fat guy's head in that now infamous Internet video.
The largest projectiles by weight and diameter are probably from custom "Howdah" guns from the late 1800's to early 1900's. Some of them were measured in "bore" like a shotgun, rather than caliber. Some custom ones were .68, even .70 caliber. They are called Howdah pistols because they were meant as last-ditch Tiger defense for English big-game hunters hunting Tigers in India from a Howdah, the little saddle/cubicle atop an elephant. However, I would suspect that the .600NE, and .50 BMG while firing lighter weight projectiles would probably still have higher velocity so more foot-pounds at the muzzle.