He'll look to avenge an earlier loss to the New York Yankees and pick up his first victory as he takes the mound at home in Wednesday's night's series finale.
Santiago (0-5, 5.01 ERA) was acquired from the Chicago White Sox in December in a three-team trade that sent outfielder Mark Trumbo to Arizona. He's given up at least four runs in four of his six starts, taking the loss in his last three.
The left-hander allowed four runs and six hits in 4 1-3 innings of a 4-3 loss to the Yankees on April 26 before yielding five runs over six innings of Friday's 5-2 loss to Texas.
Santiago is staying positive, though he knows he needs to be better.
''I don't want to say I'm not worried about my record - 0-5 is definitely a tough start,'' Santiago said. ''With the White Sox last year I was 4-9 and I had a lot of losses. Some of the games, one swing of the bat, one shift or one groundball could've been the game-changer for sure.''
Santiago's teammates are behind him as well.
''He knows he wants to get that first win off his back," catcher Hank Conger said. "I think this experience is going to be a good test for him, and a good challenge for him to try to harness what he took out of this start and take it into the next one.''
Santiago is 1-1 with a 7.71 ERA in two starts and two relief appearances against the Yankees. Derek Jeter is 3 for 5 with a home run and Alfonso Soriano is 4 for 9 with two homers and a double off Santiago, who again will oppose Vidal Nuno in this contest.
Nuno (0-0, 6.87) gave up three runs in 4 1-3 innings in the previous matchup, then allowed four runs and walked three in 4 2-3 of Friday's 10-5, 14-inning loss to Tampa Bay.
The left-hander has walked seven over 14 innings in his three starts and hasn't made it past the fifth in any of them.
"(Nuno) did OK. He gave us almost five innings," manager Joe Girardi said. "We lose a ball in the twilight, which led to a couple of runs for them, which is unfortunate, but I thought he threw the ball OK."
Nuno allowed a homer to Mike Trout in his last start against the Angels, marking the only time he's faced them in his short career.
Trout snapped a 0-for-12 slump with a triple in the eighth inning Tuesday, then scored to tie the game on Albert Pujols' single for the Angels (16-16). Brian Roberts answered with a homer in the ninth, though, to give the Yankees a 4-3 victory.
Roberts hit .156 over his first 15 games, but he's hit .340 in the 12 since for New York (17-15), which had lost five of six.
''I feel like I've gotten a lot more comfortable," Roberts said. "Sometimes, some things just click. It's been nice to get something going a little bit.''
Pujols is hitting .357 with four homers and 12 RBIs over his last 13, extending his hitting streak to seven with two hits Tuesday. Since joining the Angels in 2012, he's hitting .386 in 17 games against the Yankees, who have won seven of the last 10 meetings.