Santana (15-5) struck out eight in 7 1/3 innings, allowing one run and six hits.
"He's as consistent as any pitcher I've seen," Angels manager Mike Scioscia said. "He's approaching 30 starts, and he's throwing as well as he did in start five or six."
Santana, who won his first six decisions this year, is 4-0 in seven starts since July 27.
"It's about working hard," he said. "You just have to keep it up and keep throwing."
Detroit (67-73), which hasn't been at .500 since Aug. 2, advanced just two runners past first base before Curtis Granderson's homer in the eighth.
Mark Teixeira and Juan Rivera each drove in a pair of runs for the Angels, who broke open the game with a four-run third inning off Kenny Rogers (9-13). Gary Matthews Jr. hit safely in his first four at-bats, his first four-hit game since June 9.
Rogers (9-13) was removed after he gave up four straight singles starting the third inning, his shortest start since he gave up seven runs and got just two outs at Cleveland on July 25, 2006. The 43-year-old left-hander, who allowed six runs and eight hits in two innings, has lost three straight starts and seven of eight.
"I'm not tired. I feel fine," he said. "I had no reason for failing. I went out there and didn't get it done. That's the only way to look at it. Everything they hit went for a double or single or whatever. I just couldn't stem the tide."
Tigers manager Jim Leyland thought Rogers is fighting some nagging pain, but didn't think the pitcher would admit it.
"He won't make excuses. He's a professional," Leyland said.
Run-scoring singles by Teixeira in the first and Rivera in the second built the Angels' early lead. Robb Quinlan and Teixeira hit run-scoring singles in the third, chasing Rogers, and Vladimir Guerrero and Rivera singled in runs off Aquilino Lopez.
Hunter homered in the eighth off Nate Robertson, reaching 20 homers for the third consecutive season and seventh time in eight years. The drive landed an estimated 435 feet away in the upper hedgerow at Comerica Park.
"That's the longest ball I've ever hit here," said Hunter, who made frequent stops in Detroit during his first seven full seasons in the majors with Minnesota.
- Teixeira tumbled over the tarp after making a catch in foul territory in the second but remained in the game. He said he had a slight headache, but no physical pain.
- Detroit's Magglio Ordonez, the designated hitter for just the ninth time this season, extended his hitting streak to nine games.
- Dusty Ryan made his major league debut when he replaced Tigers C Brandon Inge in the ninth.