The Giants drafted Cain out of high school in 2002, and he made his MLB debut at age 20 in 2005, becoming the youngest player in the National League (NL) that year.

[3] As a senior at Houston High School, Cain struck out 83 batters in 62 innings pitched while recording a 1.03 earned run average (ERA).

[7] Cain attended spring training in 2005, but he began the season with the Fresno Grizzlies of the Triple-A Pacific Coast League (PCL).

He finished fifth (tied with R. A. Dickey and Adam Wainwright) in the PCL in wins and fourth with a 4.39 ERA (behind Kevin Jarvis's 3.38, Chris Oxspring's 4.03, and Édgar González's 4.37).

[13] On September 4 at Bank One Ballpark, in a 3–2 win over the Arizona Diamondbacks, Cain allowed one run in seven innings, earning his first career Major League victory.

On August 23 at AT&T Park, in an 4–1 win over the Chicago Cubs, Cain hit second career Major League home run, a fly ball two-run home run to deep left field off of starting pitcher Carlos Zambrano in the bottom of the sixth inning, scoring catcher Guillermo Rodríguez and making the score 4–0.

In addition, Cain hit a solo home run on the first pitch he saw to deep left field off of starting pitcher Todd Wellemeyer in the bottom of the sixth inning, breaking a scoreless tie and making the score 1–0.

He hit a solo home run on the first pitch he saw down the deep left field line off of starting pitcher Brandon Backe in the bottom of the fifth inning, making the score 4–1.

His 14 losses were tied for fourth in the league with Johnny Cueto, Backe, Braden Looper, and Zach Duke (behind teammate Barry Zito's and Aaron Harang's 17 and John Lannan's 15); he was one of eight NL pitchers to make 34 starts.

[9] On May 17 at AT&T Park, in a 2–0 win over the New York Mets, Cain threw six shutout innings and hit an RBI line drive single off of starting pitcher Mike Pelfrey into short left-center field, knocking in center fielder Aaron Rowand for the final run to make the score 2–0.

[45] On September 25 at AT&T Park, before a home game against the Chicago Cubs, Cain was named the recipient and 2009 Willie Mac Award winner during a pregame ceremony.

On October 8 at AT&T Park, in Game 2 of the 2010 National League Division Series against the Atlanta Braves, Cain allowed one unearned run in 6+2⁄3 innings in his playoff debut.

[57] On October 28 at AT&T Park, in a 9–0 win over the American League Champion Texas Rangers in Game 2 of the 2010 World Series, Cain capped an impressive postseason performance by pitching 7+2⁄3 scoreless innings.

[73][74][75] Following a dominant first half, Cain was selected to the All-Star Game and was chosen by manager Tony La Russa to be the NL's starting pitcher.

On July 10 at Kauffman Stadium, Cain allowed a leadoff single to Derek Jeter before retiring the six remaining hitters he faced; he was the winning pitcher in an 8–0 decision.

[76] On July 21, Cain hit his sixth career home run, off of Phillies' pitcher Cole Hamels in the third inning of a 10-inning, 6–5 Giants' victory.

[88] On August 23 against the Pirates, Cain was hit by Gaby Sánchez's line drive in the pitching arm,[89] and was placed on the 15-day disabled list for the first time in his career.

On July 4 at Petco Park, Cain struck out San Diego Padres first baseman Tommy Medica looking to end the bottom of the fourth inning for his 1,500th career strikeout, becoming the eighth pitcher in franchise history and the fourth pitcher in the San Francisco Era after Juan Marichal, Gaylord Perry, and Tim Lincecum to reach the milestone.

[94] The Giants acquired Jake Peavy a few days before the trade deadline to fill in as a starting pitcher[95] and went on to win the 2014 World Series in seven games over the American League Champion Kansas City Royals.

In that span, the San Francisco Giants are the only Major League team to accomplish both feats, according to NBC Sports Bay Area.

[103] On July 24 at AT&T Park against the Pittsburgh Pirates, Cain struck out his 1,678th career batter, surpassing Carl Hubbell for fifth place in franchise history.

He made several appearances in relief during the second half of the 2017 season and recorded his first career Major League hold in August against the Milwaukee Brewers.

[106] On September 30 at AT&T Park, Cain pitched five shutout innings against the San Diego Padres in his final career Major League start and game.

[107] On October 1 at AT&T Park, at the conclusion of Fan Appreciation Day and Weekend, the team reflected on the season and paid tribute with final goodbyes to Cain.

The event was broadcast live on local television on NBC Sports Bay Area, and included speeches from president and chief executive officer Larry Baer, manager Bruce Bochy, and battery mate and catcher Buster Posey, before an emotional Cain addressed the crowd.

[112] On July 28, 2018 outside AT&T Park, Cain and former teammates Ryan Vogelsong and Brian Wilson were all inducted onto the San Francisco Giants Wall of Fame.

[113] Cain met his wife Chelsea Williams during spring training while she was a student at Arizona State University majoring in sociology.

Prior to his perfect game, Cain and professional golfer Dustin Johnson hit golf balls from home plate into McCovey Cove.

[118] He was inspired by the success of the organization's Greater Bay Area work with five-year-old Miles Scott dressing up as Batman and becoming "Batkid" for the day and saving San Francisco.

[119] On April 8, 2014 at AT&T Park, in the Giants home opener, a 7–3 win over the Arizona Diamondbacks, Batkid rode in from left field in his Batmobile and threw out the ceremonial first pitch to Cain.