Pence was named NL Player of the Month for September, hitting .293 with a .393 on-base percentage and 11 home runs and 32 RBIs. On September 10, Pence hit his 20th home run in the 1st inning and became the 7th San Francisco Giants player to hit 20 home runs and steal 20 bases in the same season and the first since Barry Bonds in 1998. (Bobby Bonds, Willie Mays, Jeffrey Leonard, Orlando Cepeda, and Glenallen Hill are the others.) On September 14, Pence lifted his first career Giants grand slam over the center-field wall at Dodgers Stadium in Los Angeles off of Los Angeles Dodgers relief pitcher Stephen Fife and drove in a career-high 7 RBIs, helping propel the Giants to a historic 19–3 rout of their longtime rival the Dodgers. With the help of Brandon Belt’s first career five-hit game, they scored the most runs in the history of Dodger Stadium. On September 16, Pence was named National League Player of the Week for the third time in his career, after hitting .448 with 6 home runs and 19 RBIs.

He transferred to the University of Texas at Arlington (UTA) where he returned to the outfield for the UT Arlington Mavericks. He hit .347 as a sophomore in 2003 and was named a first-team all-conference outfielder. Despite missing 15 of UTA’s 30 Southland Conference games the following year due to an injury at mid-season, he was still named the 2004 Southland Conference player of the year, leading the league with a .395 batting average. Pence still holds the conference record for doubles in a single series, with 5.

Pence was drafted by the Milwaukee Brewers in the 40th round of the 2002 Major League Baseball Draft, but did not sign. In the 2004 Major League Baseball Draft he was drafted in the second round (64th pick overall) by the Houston Astros out of the University of Texas at Arlington. He played the 2004 season with the single A Tri-City ValleyCats in Troy, New York. During that year, Pence, along with current major leaguer Ben Zobrist helped lead the ‘Cats to a 50-win season in the New York–Penn League, the second-most in ValleyCats history. That year, the ‘Cats defeated the Brooklyn Cyclones in the first round, but lost to the Mahoning Valley Scrappers in the league championship.

In 2006 with the AA Corpus Christi Hooks, Pence batted .283/.357/.533 and hit 28 home runs, with 95 RBIs. He had 17 stolen bases, while being caught stealing only 4 times. In 2006, he was one of three outfielders named to the Baseball America Minor League All-Star Team. Pence began the 2007 season as the AAA Round Rock Express’ center fielder, though he made a serious run to make the big league club out of spring training.

Pence made his major league debut as the Houston Astros center fielder on April 28, 2007, versus the Milwaukee Brewers and got his first major league hit and scored his first run. Pence’s first home run in the majors was a grand slam, against the St. Louis Cardinals on May 5. Pence hit a dramatic walk-off home run against José Mesa of the Philadelphia Phillies in the bottom of the 13th inning at Minute Maid Park on July 3 in a 5–4 win. It was Mesa’s only pitch of the game. Pence was named National League co-Player of the Week for May 14–20, after recording a 1.091 slugging percentage and .625 on-base percentage with 2 home runs and 5 RBIs.

On July 29, 2011, the Houston Astros traded Pence to the Philadelphia Phillies for four minor-league players: first baseman Jonathan Singleton, right-handers Jarred Cosart and Josh Zeid, and a player to be named later, determined to be outfielder Domingo Santana. On August 4, Pence hit his first home run as a Phillie, against Madison Bumgarner.

On July 31, 2012, the Phillies sent Pence in a deadline deal to the San Francisco Giants. In return, the Phillies received Nate Schierholtz, Tommy Joseph, and Seth Rosin. On August 12, Pence hit his first home run as a Giant off Rockies’ relief pitcher Rafael Betancourt. On August 21, despite Pence no longer being on the team, the Phillies went ahead with a previously-planned Hunter Pence bobblehead promotion.

On July 13, 2013, Pence had a five-RBI game in a 9–0 Giants win over the San Diego Padres at Petco Park. With two outs in the bottom of the 8th inning, Pence robbed Jedd Gyorko of a hit by making a diving catch to preserve Tim Lincecum’s no-hitter. On August 27, Pence hit what, at the time, was the longest home run of the season to date. The ball hit a wall above the left field bleacher seats at Coors Field. According to ESPN Tracking, the ball traveled an estimated 476 feet.

During the 2013 season, Pence kept to a strict Paleolithic diet. There have been conflicting reports since about his retention of this diet.

Also in 2013 he was diagnosed with Scheuermann’s disease, a spinal disorder that usually develops in adolescence. It was not discovered in Pence until his physical before signing a five-year $90 million contract with the San Francisco Giants in September.

On March 5, 2015, Pence suffered a fractured left forearm after being hit by a pitch during a spring training game against the Chicago Cubs. He started the regular season on the disabled list, ending his league-leading iron man streak of consecutive games played at 383. Pence started a rehab assignment with the Triple-A Sacramento River Cats on May 8 and was activated from the disabled list on May 16. Pence batted .282 with two home runs and 13 RBIs in 18 games before returning to the disabled list on June 11 with left wrist tendinitis.

On December 3, 2015, Pence announced his engagement to Alexis Cozombolidis, to whom he proposed at Walt Disney World. They married on November 26, 2016.

Pence is the San Francisco host for Big League Impact, an eight-city fantasy football network created and led by longtime St. Louis Cardinals pitcher Adam Wainwright. In 2015, the organization raised more than $1 million for various charitable organizations.

Pence was named National League Player of the Week for the fourth time in his career after batting .421 (8-for-19) with 2 home runs and 10 RBIs during April 25 – May 1, 2016. On May 14, Pence hit his 200th career home run in a game against the Arizona Diamondbacks. On June 1, Pence suffered a torn hamstring tendon of his right leg while running to first base, and was expected to miss at least eight weeks. In 2016 he batted .289/.357/.451 with 13 home runs in 395 at bats.

Pence appeared as himself in an episode of the television sitcom Fuller House in 2016. Pence appeared as a guest on an episode of Bill Nye Saves the World in 2017.

On May 15, 2017, Pence was placed on the 10-day disabled list due to a troubling left hamstring. For the season, he had the lowest line drive percentage of all major league hitters (13.4%). In 2017 he batted .260/.315/.385 with 13 home runs in 493 at bats.

On April 3, 2018, Pence sprained his thumb while diving to make a play. Pence was placed on the 10-day disabled list due to the injury. In 2018 he batted .226/.258/.332 with 4 home runs in 235 at bats.

On February 7, 2019, Pence signed a minor league contract with an invitation to spring training with the Texas Rangers. On March 21, the Rangers announced that Pence made the Opening Day roster. Pence was voted in as the starting designated hitter for the American League in the 2019 Major League Baseball All-Star Game. Pence finished the 2019 season posting a .297/.358/.552/.910 slash line with 18 home runs and 59 RBIs over 286 at bats in 83 games.

On February 7, 2020, Pence re-signed with the Giants on a one-year, $3 million contract. After starting the season by hitting .096/.161/.250 with 2 home runs and 6 RBIs over 56 plate appearances, Pence was designated for assignment on August 23, 2020, after the team’s acquisition of Daniel Robertson. He was released by the Giants the next day.

On September 26, 2020, Pence officially announced his retirement from professional baseball.