Selected to the MLB All-Star Game in 2007, he won that year's American League (AL) earned run average (ERA) title.

After missing the 2012 season due to ulnar collateral ligament reconstruction surgery in his pitching elbow, and helping the Red Sox win the 2013 World Series, Lackey was named the winner of the Tony Conigliaro Award.

A right-handed pitcher and batter, the Anaheim Angels selected Lackey from Grayson County College in Texas in the 1999 amateur draft.

Known for his intense competitiveness and overall durability, Lackey reached at least 200 innings pitched six times in his career, and in five seasons was in the top ten in games started.

He began his professional career with the Boise Hawks in the Short Season Class A Northwest League, posting a 6–2 record and a 4.98 ERA.

'"[2] In 2000, Lackey split his time between the Single-A Cedar Rapids Kernels, High-A Lake Elsinore Storm, and Double-A Erie SeaWolves.

He began 2001 with Double-A Arkansas before being promoted in July of that year to the Triple-A Salt Lake Stingers, where he struggled a bit, posting a 3–4 record and a 6.71 ERA.

With the AL Wild Card in hand, the Angels began their march through the 2002 postseason, facing the New York Yankees in the American League Division Series (ALDS).

He made his relief and postseason debut in Game 3, allowing two earned runs in the midst of an Angels rally to win 9–6.

He gained his first postseason victory against the Minnesota Twins in Game 4 of the American League Championship Series (ALCS), pitching seven innings while allowing only three hits and striking out seven.

However, in Game 7 of the World Series on October 27, 2002, Lackey allowed one earned run on four hits while striking out four in five innings,[4] allowing the Angels to hold an early 4–1 lead to hand over to their bullpen trio of Brendan Donnelly, Francisco Rodríguez, and Troy Percival to seal their World Series title.

Lackey became only the second rookie in World Series history to start and win Game 7, the other being Babe Adams of the 1909 Pittsburgh Pirates.

[6] Mike Scioscia announced that Lackey would start on Opening Day 2003, replacing injured ace Jarrod Washburn.

[7] Lackey struggled his sophomore year, compiling a 10–16 record with a 4.63 ERA while leading the team in hits and earned runs allowed, and wild pitches.

[1] After the Angels placed 2005 Cy Young winner Bartolo Colón on the disabled list in 2006, Lackey emerged as the team's ace, and skipper Mike Scioscia made him the number one starter after the All-Star break.

In Game 1 of the 2008 ALDS, he gave up a two-run home run to Jason Bay of the Red Sox, and was charged with the Angels' first loss in the series.

[13] On August 30, 2009, Lackey earned his 100th career win against the Oakland Athletics, giving up one run (on an error by shortstop Erick Aybar) through eight innings.

Lackey is one of only six major league pitchers who won at least 11 games in each year from 2004 to 2009, the others being CC Sabathia, Derek Lowe, Johan Santana, Javier Vázquez, and Jason Marquis.

[20] On April 7, 2010, Lackey made his debut for Boston at Fenway Park against the Yankees, pitching six innings of three-hit, shutout ball.

The 114 earned runs he allowed were the most in the American League,[24] and his ERA was the highest in Red Sox history for a starter with at least 150 innings pitched.

In the end of the 2011 season, Lackey and two more starting pitchers (Josh Beckett and Jon Lester, allegedly) were in the center of a controversy that told that the three (and sometimes more) drank beers and ate fried chicken in the clubhouse during games in which they were not pitching.

In doing so, Lackey became the first starting pitcher in Major League history to win two World Series "clinching" games with two different teams.

[33] Many credited Lackey's turnaround as a major reason for the Red Sox' success in 2013, especially at mid-season when Clay Buchholz went on the disabled list and Jon Lester was going through a rough stretch.

Instead of retiring and foregoing being paid the league minimum, Lackey had stated in the previous August that he would pitch in 2015 if the Cardinals picked up the option that actuated because he missed the 2012 season due to Tommy John surgery.

[46] By earning his 10th win of 2015 in a 6–2 defeat of the Miami Marlins on August 15, Lackey recorded his 12th consecutive season of double-digit victory totals.

[43] Further, Lackey turned in a season that exceeded his career norms, including a career-best 2.77 ERA, seventh-best in the league, and recorded 218 IP, his highest total since 2010.

He opposed Jon Lester — both men had faced the Cardinals in the World Series two years earlier as teammates with the Red Sox.

[57] He joined Al Leiter, Randy Johnson, Kevin Brown, Barry Zito, Terry Mulholland, Curt Schilling, Woody Williams, Jamie Moyer, Javier Vázquez, Vicente Padilla, Derek Lowe, Dan Haren, A. J. Burnett, Kyle Lohse, and Tim Hudson as the only players to achieve this milestone.

On August 30, 2011, Lackey filed for divorce from Krista, his wife of almost three years, who had been battling cancer since March and underwent chemotherapy through June.

He was featured in a 2011 Kevin Fowler music video alongside fellow Red Sox starting pitchers Josh Beckett, Jon Lester, Tim Wakefield, and Clay Buchholz.