Note: no designated hitter (DH), per the rules at this time, due to playing in a National League park April 6–9, in Philadelphia On April 6, right after the opening day game against the Phillies, the Red Sox announced that they signed free-agent-to-be RHP Rick Porcello to a four-year, $82.5 million contract extension through 2019, contradicting an earlier report, that both parties won't engage in contract negotiations during the season.

Game 3: Clay Buchholz could not repeat his stellar opening day outing, allowing 10 runs (9 earned) in 3 1/3 innings and the Red Sox dropped the series finale 4–14 in the Bronx.

In the bottom of the ninth Mike Napoli drew a lead-off walk, Daniel Nava moved him in scoring position with a sacrifice bunt and Xander Bogaerts drove him in with a bloop single for the first Boston walk-off of the season.

Again with two outs Pablo Sandoval walked, Allen Craig reached on an error by Machado and Brock Holt hit a three-run shot in the top of the eighth, his first home run of the season.

Red Sox lost the series 1–2 (18–28 runs) April 27–29, vs. Toronto Game 1: Mookie Betts capped his three-hit night with a walk-off single in the bottom of the ninth against the Blue Jays.

Allen Craig hit his first home run of the season and Boston fell victim to fan interference in the bottom of the fourth, when a spectator in a Red Sox jacket reached over and deflected a Ryan Hanigan double, which could have scored Xander Bogaerts from first.

Game 3: Joe Kelly was pulled after 4 2/3 innings and the slide continued for Boston, falling under .500 for the first time this season, when New York scored eight runs before the Red Sox could assemble a five-run bottom of the sixth.

With Ryan Hanigan heading to the 60-day disabled list, Boston claimed Luis Jiménez off of waivers from the Brewers and added him to the 25-man roster, sending down Dalier Hinojosa to Pawtucket.

Game 2: A stellar eight-inning, three-hit, one-run outing by Clay Buchholz went for naught, when the offense could provide only one run of support, an RBI triple by Xander Bogaerts.

The Red Sox headed back home from the ten-game road trip, and while the struggling pitching stabilized the offense went quiet, scoring only 23 runs in this ten game stretch.

Anthony Varvaro, who was designated for assignment on April 29 and claimed by Cubs on May 3, was returned to Boston and put on the disabled list due to a torn flexor tendon.

Hanley Ramírez hit his first home run since April 29, Blake Swihart drove in two, Rusney Castillo collected his first RBI of the season, and Dustin Pedroia and Mookie Betts both had a three-hit night.

Game 3: The Red Sox could not get to Athletics' starter Kendall Graveman until Rusney Castillo hit his first home run of the season off of him and he was pulled in the bottom of the eighth.

Red Sox won the series 3–0 (15–8 runs) June 9–11, in Baltimore Game 1: Eduardo Rodríguez gave up three hits and three walks in six innings of shutout ball but received no run-support.

Red Sox lost the series 0–3 (7–12 runs) June 12–14, vs. Toronto Game 1: Matt Barnes, Junichi Tazawa and Tommy Layne gave up six straight hits and allowed nine batters to reach base safely, who all scored, without recording an out in the top of the seventh.

With the bases loaded and one out in the bottom of the seventh, Boston could not cash in and the game headed into extra innings where Russell Martin put the Blue Jays on top for good.

Holt doubled to deep left in the first, singled to right in the fifth, homered over the Monster in the seventh, and hit a ringing triple into right center in the eighth to complete the cycle, the first in the majors this year.

In a series of roster moves, Eric Kratz was designated for assignment, Joe Kelly was optioned to Pawtucket, putting Justin Masterson back in the rotation, and Jackie Bradley Jr. got the call-up among three others.

Red Sox won the series 2–1 (10–10 runs) June 29 – July 2, in Toronto Game 1: Clay Buchholz pitched eight innings of one-run ball, Mookie Betts scored twice and Xander Bogaerts drove in two.

Hanley Ramírez homered for two runs in the fourth, to put Boston on top, Mookie Betts and Xander Bogaerts added insurance in the seventh with a two-out RBI each.

Red Sox lost the series 1–2 (12–16 runs) July 17–20, in Anaheim Game 1: Wade Miley took a no-hitter into the seventh inning but gave up a lead-off double to Kole Calhoun.

The Red Sox could not take advantage and in the bottom of the ninth on their second hit of the night, Mike Trout took Koji Uehara deep for the lone run of the game.

Game 3: On the day of the induction of former Red Sox pitcher Pedro Martínez into the Hall of Fame, David Ortiz collected a career-high seven RBI including two three-run shots in the fifth and in the seventh inning.

Game 4: Led by a stellar performance by Steven Wright, two runs in a career high seven innings, the Red Sox avoided the sweep, scoring seven times off of Chris Sale.

Game 1: Mike Napoli put the Red Sox on top for good with a two-run home run in the bottom of the seventh and Blake Swihart added insurance in the eighth on a wild pitch.

Boston's offense was provided by a home run off the bat of David Ortiz in the fourth and an RBI double by Alejandro De Aza, after Mike Napoli reached second base on a throwing error in the second inning.

Red Sox lost the series 1–2 (6–16 runs) August 7–9, in Detroit Game 1: Joe Kelly won back-to-back outings for the first time since the end of last season.

Earlier this day, Dennis and Callahan cited multiple sources, that Don Orsillo, play-by-play commentator for Red Sox baseball on NESN since 2001, will not return in 2016.

David Ortiz homered for the fourth time in the last eight games and Xander Bogaerts hit a little league grand slam on a bases clearing double and a throwing error by second baseman César Hernández.

Game 3: With two outs in the third inning, Mookie Betts went deep, which was initially ruled a double but after an umpire review the call on the field was overturned, Dustin Pedroia and Xander Bogaerts both singled and David Ortiz launched his 498th career-home run.