American League

1. Boston Red Sox – AL East champions, 96–66 (5–2 head-to-head record vs. CLE)^[2]
2. Cleveland Indians – AL Central champions, 96–66 (2–5 head-to-head record vs. BOS)^[3]
3. Los Angeles Angels of Anaheim – AL West champions, 94–68^[4]
4. New York Yankees – 94–68^[5]

National League

1. Arizona Diamondbacks – NL West champions, 90–72^[6]
2. Philadelphia Phillies – NL East champions, 89–73^[7]
3. Chicago Cubs – NL Central champions, 85–77^[8]
4. Colorado Rockies – NL Wild Card qualifier, 90–73^[9][10]

(1) Boston Red Sox vs. (3) Los Angeles Angels of Anaheim

Boston won the series, 3–0.

This was the third postseason meeting between the Angels and Red Sox. The Red Sox once again defeated the Angels to advance to the ALCS for the third time in five years. The series was not close — the Red Sox shut out the Angels and Game 1, took Game 2 by a 6–3 score on a Manny Ramirez walk-off three-run home run, and then blew out the Angels in Anaheim in Game 3 to advance to the next round.

(2) Cleveland Indians vs. (4) New York Yankees

Cleveland won the series, 3–1.

This was the third postseason meeting between the Yankees and Indians. The Indians defeated the Yankees in four games to advance to the ALCS for the first time since 1998. This was the last postseason series ever played at the original Yankee Stadium.

The Indians blew out the Yankees in Game 1 by 9 runs. Game 2 was a pitchers' duel between both teams bullpens which lasted 11 innings, and again the Indians prevailed as Travis Hafner drove in the winning run on a bases-loaded single off Luis Vizcaíno. Game 2 was referred to as "The Bug Game", as a swarm of tiny insects circled the mound in the late innings of the game. Play was stopped temporarily out of concern for the players' safety, including Joba Chamberlain, who threw only 12 of his 25 pitches for strikes in suffering a blown save without surrendering a hit. Yankees manager Joe Torre would later say that his decision not to remove his team from the field was one of his biggest regrets as a manager.^[18] When the series shifted to the Bronx for Game 3, the Yankees overcame a 3–1 Indians lead to win 8–4 to stave off elimination. The Yankees put up another rally late in Game 4, but the Indians held on to win by a 6–4 score to advance to the ALCS.

The loss to the Indians marked the end of the Yankees' thirteen-year postseason streak, which started in 1995. The Yankees' thirteen-year postseason appearance streak is the longest of any American League team, and second only to the Atlanta Braves, who made fourteen straight appearances from 1991 to 2005.

(1) Arizona Diamondbacks vs. (3) Chicago Cubs

Arizona won the series, 3–0.

The Diamondbacks swept the Cubs to return to the NLCS for the first time since 2001.

In Game 1, the Diamondbacks prevailed by a 3–1 score thanks to a solid pitching performance from Brandon Webb. The Diamondbacks would put up a big lead early in Game 2 and didn't relinquish it, winning 8–4 to take a 2–0 series lead headed to Chicago. Liván Hernández kept the Cubs' offense at bay in Game 3 as the Diamondbacks won 5–1 to return to the NLCS.

This was the most recent playoff series win by the Diamondbacks until 2023. They would, however, win the NL Wild Card Game in 2017.

(2) Philadelphia Phillies vs. (4) Colorado Rockies

Colorado won the series, 3–0.

This was the first postseason meeting between the Phillies and Rockies. The Rockies swept the Phillies to advance to the NLCS for the first time in franchise history. These two teams would meet once more in the 2009 NLDS, which the Phillies won in four games.

(1) Boston Red Sox vs. (2) Cleveland Indians

Boston won the series, 4–3.

This was the fourth postseason meeting between the Indians and Red Sox (1995, 1998, 1999). The Red Sox came back from a 3-1 series deficit to return to the World Series for the second time in four years.

Similar to 2004, the Red Sox once again found themselves trailing in the series. The Red Sox blew out the Indians in Game 1, while the Indians evened the series in a 13-6 rout thanks to help from Jhonny Peralta, Grady Sizemore, and Franklin Gutiérrez. When the series shifted to Cleveland for Game 3, Jake Westbrook out-dueled Boston ace Daisuke Matsuzaka as the Indians prevailed by a 4-2 score to take the series lead. The Indians' offense would chase Tim Wakefield from the mound in Game 4 thanks to a seven run fifth inning to take a 3-1 series lead, and were now one win away from their first World Series berth in a decade. However, things then unraveled for the Indians fast. In Game 5, Josh Beckett out-dueled CC Sabathia as the Red Sox blew out the Indians to send the series back to Fenway Park. Curt Schilling and the Red Sox bullpen would shut down the Indians offense in Game 6 as the Red Sox blew out the Indians by a 12-2 score to force a seventh game. The Red Sox's ten run margin of victory was the largest in an LCS game since Game 4 of the 1974 NLCS. In Game 7, the Red Sox again blew out the Indians, this time by nine runs, to clinch the pennant.

The Red Sox would win their next AL pennant in 2013, against the Detroit Tigers in six games. The Indians wouldn't return to the ALCS again until 2016, where they defeated the Toronto Blue Jays in five games before falling in the World Series that year.

The Indians would not return to the postseason again until 2013. Both teams would meet again in the 2016 ALDS, which the Indians won en route to the World Series.

(1) Arizona Diamondbacks vs. (4) Colorado Rockies

Colorado won the series, 4–0.

This was the first postseason meeting between the Diamondbacks and Rockies. The Rockies swept the top-seeded Diamondbacks to advance to the World Series for the first time in franchise history.

Jeff Francis pitched over six solid innings as the Rockies stole Game 1 in Phoenix. Game 1 was marred by a controversial call in the bottom of the seventh inning - Francis allowed a leadoff double to Chris Snyder and hit Justin Upton with a pitch, but the Diamondbacks were taken out of a potential rally when a disputed interference call resulted in a double-play groundout for Augie Ojeda. Diamondbacks fans responded by throwing objects onto the field, which stopped play. The Rockies would then prevail in a long 11-inning affair in Game 2 to go up 2-0 in the series headed home to Denver. Home runs from Matt Holliday and Yorvit Torrealba would carry the Rockies to victory in Game 3. Holliday would again hit another three-run home run in Game 4 to give the Rockies a big lead that they would hold onto, as they clinched the pennant in front of their home fans.

By sweeping the series, the Rockies became the first team since the 1976 Cincinnati Reds to start 7–0 in the postseason. The Diamondbacks would not return to the postseason again until 2011, and this was their last appearance in the NLCS until 2023, where they defeated the Philadelphia Phillies in seven games to return to the World Series.

Both these teams would meet again in the 2017 NL Wild Card Game, which was won by the Diamondbacks.

(AL1) Boston Red Sox vs. (NL4) Colorado Rockies

Boston won the series, 4–0.

This was the first World Series ever played in the state of Colorado. It was also the sixth World Series in a row to feature a Wild Card team. The Red Sox handily swept the Rockies to win their second title in four years and seventh overall.

The series was heavily lopsided in favor of the Red Sox - Josh Beckett pitched seven solid innings and gave up only one run as the Red Sox blew out the Rockies by a 13-1 score in Game 1. The Rockies took an early lead in Game 2, but the Red Sox put up two unanswered runs across the fourth and fifth innings to take the lead, and Curt Schilling and the Red Sox bullpen would keep the Rockies' offense at bay the rest of the game to go up 2-0 in the series headed to Denver. The Red Sox offense would once again explode for 10 runs in Game 3 as they won 10-5 to take a 3-0 series lead. The Sox would then clinch the title in Game 4 as Jonathan Papelbon fended off a late rally by the Rockies.

The Rockies would return to the postseason again in 2009, but fell to the Philadelphia Phillies in the NLDS. The Red Sox attempted to defend their title the next year, but fell to the Tampa Bay Rays in seven games in the ALCS. They would win the World Series twice more afterward - in 2013, where they defeated the St. Louis Cardinals in six games, as well as 2018 where they defeated the Los Angeles Dodgers in five games.