Santana led off the tenth inning with a single, he moved to third on a single from Brian Dozier. With runners at the corners and no one out the Indians walked Joe Mauer to load the bases. Plouffe then connected on a looping single into center field to win the game.
It was the second walk-off win for the Twins this week, they beat Detroit in walk-off fashion on Tuesday night.
The Twins tied the game in the ninth when Cleveland shortstop Jose Ramirez misplayed what could have been a game-ending double play ball allowing Eduardo Nunez to score to tie the game at four.
Twins starter Phil Hughes didn't have his best outing of the season. Cleveland put up four runs on 10 hits on the Twins righty, but Hughes continued on his historic pace, he struck out five and didn't walk a batter in seven innings to improve his strike-to-walk ratio.
Jared Burton (3-5) recorded the final two outs in the top of the 10th for the win, while Kyle Crockett (4-1) was tagged with the loss.
Arcia had a big night, he was 3-for-4 with a home run and two RBIs. Kennys Vargas also homered, but it was Plouffe, who came up with the biggest hit of the night – his only one.
The Twins and Indians continue the series on Saturday night at Target Field. Trevor May starts on the mound for Minnesota against Cleveland's T.J. House.