The Phillies announced, following the 2009 World Series, that they would pick up their 1-year, $9 million option on starting pitcher Cliff Lee, who posted a 4–0 record in the previous postseason.

[1] General manager Rubén Amaro Jr. informed pitcher Brett Myers, who had started and relieved in 2009 and sustained several injuries, that the Phillies would not pursue him for a new contract if he filed for free agency.

In a related deal, the Phillies traded three prospects to the Toronto Blue Jays for the rights to right-handed starting pitcher Roy Halladay, as well as $6 million cash to cover the difference between the two aces' salaries.

[13] In total, the Phillies went 13–12 in spring training,[14] where a position battle occurred for the fifth spot in the starting rotation between left-handed veteran Jamie Moyer and young right-hander Kyle Kendrick.

[19] They did not complete the sweep, however, as the Nationals won the third game of the series, 6–5, after newly acquired relief pitcher Nelson Figueroa allowed an RBI double to Ryan Zimmerman in the seventh inning.

[32] The next night, Halladay posted the third straight strong performance by the Phillies' rotation, and played the role of stopper by holding the Braves scoreless on five hits to notch his second complete game of the season and the sixteenth shutout of his career.

[38] Continuing play against the National League West, Halladay started against the San Francisco Giants, but lost his first decision of the season, 5–1, as the Phillies left 22 men on base.

[44] The Phillies returned to first place in the division with an 11–5 victory in the series' final game, capped by a grand slam by Victorino; the 10 runs scored against Mets starter Johan Santana were the most allowed in a start in his career.

[54] After weather on May 11 forced a day-night doubleheader the following day, the Rockies defeated Philadelphia, 4–3, on a walk-off home run by Miguel Olivo; the second game was postponed again due to additional rain and snow.

[60] The two-game series against Pittsburgh ended in a split, however, as Halladay's two-run complete game on May 18 was overshadowed by six innings of one-run baseball pitched by Zach Duke, handing the Phillies their fourth loss of the month.

[63] Philadelphia opened interleague play against the Boston Red Sox on May 21, defeating them, 5–1; J. C. Romero collected his second save of the season to close Hamels' fifth victory, and Werth hit a home run to the second deck in left field.

[87] In the series opener against the Minnesota Twins, Howard had four hits in four at-bats, finishing a single short of the cycle and pacing the Phillies offense with two solo home runs, a triple, and a double as Philadelphia won, 9–5.

[94] Halladay faced off against his former club for the first time in the regular season, defeating Toronto, 9–0; the offense was paced by three hits and four runs batted in for Ross Gload, along with four walks from Rollins from the leadoff spot.

They lost to the Cincinnati Reds in the series opener, 7–3, as Utley sprained his right thumb sliding into second base;[97] the injury led the team to place him on the disabled list, along with Polanco, who had soreness in his elbow.

The first game of July was also the first of a four-game series against the Pirates; bench coach Pete Mackanin led the Phillies during Manuel's one-game suspension stemming from an incident with umpire C. B. Bucknor, but Philadelphia lost, 3–2.

[123] Philadelphia continued against the National League West on July 27 when they opened a series against the Diamondbacks with a 9–5 victory; Howard hit his 23rd home run, but Victorino and Rollins were both injured in the contest.

[125] After acquiring starting pitcher Roy Oswalt in a trade from the Astros for Happ, Valdez sealed Philadelphia's eighth consecutive victory with an 11th-inning single to score Cody Ransom with one out on July 29.

[131] The second game of the series marked a third straight Phillies victory, as Brown backed Kendrick's two-run effort with three runs batted in and an outfield assist to put out Marlins first baseman Gaby Sánchez at home plate.

[140] In the second game, Halladay turned the tables with an eight-inning shutout performance after the Phillies scored three unearned runs due to an error by third baseman David Wright, snapping a 38-inning scoreless streak at the Mets' home field.

[150] In the opening game of the next series against Houston, Philadelphia led, 2–1, after seven innings of play, when former Phillies outfielder Michael Bourn appeared to leave the basepath running from home plate to first base on an infield single.

After a brief on-field altercation, the Phillies, who were out of bench players, moved Ibáñez to first base and brought on Oswalt to play left field, where he made the first putout of the 15th inning on a fly ball.

On September 1, they defeated the Dodgers, 5–1, to complete their last series of the year against a National League West team; Oswalt no-hit Los Angeles through 5+2⁄3 innings and was supported by a career-high three doubles from Utley.

[161] After a one-game stop in Colorado to make up the rainout from May 11—Philadelphia won, 12–11[162]—the Phillies returned home to play their final series against the National League Central, facing the Brewers.

[165] The next series against Florida opened with a doubleheader, which the teams split; the Marlins won the day game, 7–1, behind six innings of one-hit ball from rookie Adalberto Méndez,[166] while the Phillies took the nightcap, 7–4.

However, the Phillies swept the Braves with three consecutive victories, beginning with a 3–1 win in which Hamels threw eight innings, calling the game "a chess match" and crediting his improved cut fastball and curveball.

[187] They salvaged the series victory, however, with a 7–1 win on September 29; three backup players, including Sweeney, Francisco, and John Mayberry Jr., hit home runs in the game; the Phillies finished the month 21–6.

[188] Though some, including Chipper Jones, had speculated that the final series against the Braves would decide the division,[189] Atlanta sought a wild-card berth after the Phillies had claimed the NL East crown.

[198] In the second game, the Reds' Brandon Phillips had three hits, including a double and a home run against Philadelphia starting pitcher Roy Oswalt, but also committed two of Cincinnati's four errors.

[203] In Game 3, Philadelphia was shut out in the postseason for the sixth time in franchise history; Ross batted in another run to score Édgar Rentería as the Giants defeated the Phillies, 3–0.

After the Phillies tied the game, Oswalt pitched the bottom of the ninth inning in relief and gave up a walk-off sacrifice fly to Juan Uribe.