Now the veteran right-hander has a chance to tie for the major league wins lead and get the A's back on track Friday night when he opposes Williams in Oakland.
The Angels (48-52) took the opener of this four-game set Thursday, knocking out Oakland starter Dan Straily during a four-run fifth inning and adding three more in the sixth on the way to an 8-3 victory.
After dropping the first five meetings, Los Angeles has won four of five in the season series.
The AL West-leading A's (59-43) will try to regroup with their 21st victory in 27 home games as they give the ball to Colon (13-3, 2.52 ERA). They've won 11 of his last 12 starts.
The 40-year-old All-Star, who has given up three runs or fewer in each of his last 13 outings, can match Tampa Bay's Matt Moore and Detroit's Max Scherzer for the major league lead with his 14th victory.
He'll face the Angels for the second time in six days after tossing a four-hitter in a 6-0 victory in Anaheim on Sunday. He struck out five and walked one in this third shutout of the season, tied with Cleveland's Justin Masterson for the major league lead.
"I've been trying to explain it all year and I can't,'' manager Bob Melvin said when asked about Colon's success in his 16th big league season.
Colon, who won the 2005 AL Cy Young award for the Angels, has gone 5-1 with a 1.62 ERA in his last eight starts against his former club.
Hamilton went 1 for 5 in his return to the lineup Thursday after missing three games with right ankle stiffness. He's 4 for 28 in his last six games overall.
Albert Pujols, however, kept his recent hot streak going with three hits and two RBIs in the opener. He's batting .352 with four homers and 13 RBIs over a 14-game stretch.
After hitting .111 with runners in scoring position while averaging 2.1 runs in its previous nine games, Los Angeles was 6 for 11 in those situations Thursday.
"You try not to be too aware of what's going on," said Mark Trumbo, who drove in a pair. "We know we haven't scored a ton of runs lately."
Considering Williams' struggles of late, the Angels may need to continue that timely hitting if they hope to win three in a row.
Williams (5-6, 4.73) was tagged for six runs - four earned - and eight hits over five-plus innings against the A's on Sunday, dropping to 0-3 with a 14.54 ERA in his last four starts.
The right-hander has lost his last three starts versus Oakland, yielding nine walks and three homers en route to a 6.14 ERA.
Eric Sogard homered off Williams on Sunday and is 4 for 5 lifetime in this matchup.
The A's will be without catcher John Jaso after he was placed on the seven-day concussion disabled list Thursday. Derek Norris filled in nicely Thursday, going 2 for 4 with his sixth home run.
Yoenis Cespedes suffered what Melvin called a bruise after sliding into home plate in the fourth inning. He stayed in the game, but had a wrap around his right knee in the clubhouse.