The Red Sox finished last in the five-team American League East with a record of 69 wins and 93 losses, 26 games behind the first-place New York Yankees.

[4] During an interview aired on local television on April 15, manager Bobby Valentine ripped 3B Kevin Youkilis, saying he is not "as physically or emotionally into the game as he has been in the past".

[7] After losing 4 consecutive games, the Red Sox took a 9–0 lead through 5 innings against the rival Yankees on April 21, but relief pitchers Vicente Padilla, Matt Albers, Franklin Morales, Alfredo Aceves, Justin Thomas, and Junichi Tazawa combined to allow 14 runs total in the 7th and 8th innings, as the Yankees prevailed by a score of 15–9, for the Red Sox' 5th consecutive loss.

[9] After their losing streak, the road was kind to the Red Sox, as they amassed a six-game winning streak by sweeping the Minnesota Twins in Minneapolis and taking the first three games of a four-game series against the Chicago White Sox, including scoring 9 runs in 5 innings against Philip Humber, who had thrown a perfect game in his previous start.

On May 6, the Red Sox used all of their available bullpen pitchers in the lengthy 17-inning game and had to send in outfielder Darnell McDonald to pitch,[11] ultimately leading to a 9–6 setback.

[12] The Red Sox finally saw some measurable success at Fenway over and just after Mothers' Day weekend, taking three games of four from the Cleveland Indians and sweeping a quick two-game series over the Seattle Mariners before embarking on another road trip.

During this time, McDonald went on the Disabled List, but the Red Sox recalled OF Daniel Nava and acquired OF Scott Podsednik, who had not played a Major League game since September 9, 2010.

While on the road trip, outfielders Cody Ross and Ryan Sweeney were injured, but 3B Kevin Youkilis returned from the Disabled List.

On May 26, Jarrod Saltalamacchia had a pinch-hit, two-run home run off Fernando Rodney with one out in the bottom of the ninth inning, to lift the Red Sox to a 3–2 win over the Tampa Bay Rays at Fenway Park.

The Red Sox received utility player Brent Lillibridge and pitcher Zach Stewart (who was assigned to AAA Pawtucket) in the trade.

The Sox came home to Fenway Park to face the rival Yankees in a four-game series, which included a Saturday doubleheader created to compensate for a rained out Red Sox-Yankees game earlier in the year.

Ciriaco amassed four hits and four RBIs in the Saturday night game, as his offensive prowess became the main storyline of the Red Sox' lone win of the series.

The Red Sox enjoyed this offensive prowess in spite of the loss of big hitter David Ortiz to the 15-day disabled list after injuring himself during a slide.

The Red Sox soon hit another bump in the road, however, getting swept in a vital intra-divisional series with Toronto, then proceeding to lose two of three to the Rangers.

The Sox fell as low as 49–51 but were able to close out July with a strong surge, salvaging the Saturday and Sunday games of a weekend series against the Yankees in the Bronx after losing the Friday contest, and then winning the first two games of a three-game home series against Detroit, such that the BoSox were able to close out July on a four-game winning streak.

The club as a whole was jolted by the death of Red Sox legend Johnny Pesky on Monday, August 13, 2012, at the age of 92, in hospice care in the nearby North Shore suburb of Danvers.

Oddly, David Ortiz, Clay Buchholz, Vicente Padilla, and Jarrod Saltalamacchia were the only Red Sox players who attended Pesky's funeral, only for most of the team to appear at a bowling event led by pitcher Josh Beckett later that night, which angered fans, press, and front office executives alike.

With playoff hopes looking dim, Red Sox office management decided to look ahead to the following season by freeing up money in the payroll by performing a salary dump trade that sent Adrián González, Josh Beckett, Carl Crawford, and Nick Punto to the Dodgers in exchange for James Loney and four prospects: pitchers Allen Webster and Rubby De La Rosa, infielder Ivan De Jesus Jr., and outfielder Jerry Sands.

On Labor Day, the Red Sox opened up a three-game swing in Seattle with yet another loss, bringing their losing streak to a season-worst seven games.

Boston broke yet another losing streak with a bottom-ninth victory over the rival Yankees on Tuesday, September 11, in a game wherein Jacoby Ellsbury recorded a walk-off single for the 4–3 triumph.

However, the very next day, on Sunday, September 16, the Sox fell to the Jays to put their record at 66–81, officially eliminating them, albeit unsurprisingly, from the playoff race for the third straight year.

[20][21] On Thursday, October 4, 2012, Valentine was officially fired from the position of manager of the Boston Red Sox after one season, confirming the earlier rumors.