The inconsistent first baseman looks to help the visiting Indians avoid their first series loss of the month Wednesday against the Minnesota Twins.
Although Cleveland (51-49) was expecting big things after Santana hit a career-high .268 with 20 home runs and 74 RBIs last season, the former catcher hit rock-bottom with a .136 average on May 10.
Santana appeared to turn things around by hitting .301 with eight homers over his next 31 games. Instead, he was batting .177 with two homers over a 22-game stretch heading into Tuesday's matchup at Target Field.
After the Indians had totaled four runs while dropping their last two games, Santana showed signs of life by matching a season high with four hits - including a home run and two doubles - in an 8-2 victory.
"When he's going good, it makes us a whole different lineup," said manager Terry Francona, whose club is 12-6 in July and 4-0-1 in five series since dropping two of three at Seattle from June 27-29.
Santana is batting .355 with three homers, six doubles and eight RBIs over a seven-game hitting streak in Minnesota. He's 5 for 12 with a home run all-time versus Anthony Swarzak (1-0, 4.34 ERA).
The right-hander will make his first start since October 2012 after scheduled starter Kyle Gibson was scratched. Manager Ron Gardenhire says team doctors told him Gibson's back felt tight after throwing in the bullpen.
Swarzak hasn't been sharp of late with a 7.71 ERA over seven innings in his last four appearances. He's 1-5 with a 7.34 ERA in 16 career games - including four starts - versus Cleveland.
The Indians have tagged him for five runs and nine hits over 1 1-3 innings in 2014. Asdrubal Cabrera (5 for 15), Michael Brantley (5 for 15), Lonnie Chisenhall (4 for 11) and Jason Kipnis (6 for 11) have hit well against Gibson, though Cabrera could miss a second straight game due to back spasms.
Nick Swisher, hitless in 13 career at-bats versus Swarzak, also broke out Tuesday with his first three-hit effort of the season. Yan Gomes contributed two hits, leaving him 11 for 21 with six RBIs over his last seven games.
Trevor Bauer (4-4, 3.89) is set to make his first career start against the last-place Twins (45-54) after going 2-0 with a 2.84 ERA in his last four overall - all Cleveland victories.
The right-hander, however, has gone 1-3 with a 5.29 ERA in six road starts. He didn't have his best stuff at Detroit on Friday, but earned the win after allowing three runs over six innings in a 9-3 victory.
Bauer faces a Minnesota team that has been without Joe Mauer since early July due to a strained right oblique. The Twins have totaled 12 runs while going 4 for 41 with runners in scoring position during a 1-4 stretch.
"I don't think you can point to anything," said second baseman Brian Dozier, who went 3 for 5 with his team-leading 19th home run Tuesday. "It's just basically not hitting."