Williams hit 19 of his 33 field goal attempts, including 6-for-11 from three-point range, and also connected on eight of nine tries from the free-throw line to go with seven assists.
Williams' previous single-game scoring high this season came on Nov. 28, when he scored 25 points in a one-point win over the Los Angeles Lakers.
Knicks small forward Carmelo Anthony and Bulls big man Pau Gasol had set the previous NBA high mark this season with 46 points in wins over the Jazz and Bucks, respectively.
The 32-year-old has received more playing time than expected so far this season because starter Ricky Rubio has been sidelined since early November with an ankle injury. Over 28 games this season entering Tuesday, Williams had averaged 11 points on 39.7 percent shooting with 6.6 assists.
In the same game, two Pacers were ejected. Power forward David West was flagged for two technical fouls and center Roy Hibbert was assessed a flagrant-2 for pulling down Gorgui Dieng by the uniform. The win marked the Timberwolves' first in their last 16 games and improved their record to 6-30. The Pacers fell to 15-25 and are now two games back of a playoff spot in the Eastern Conference.