Uehara graduated from the Osaka University of Health and Sport Sciences. In 1998, Uehara rejected a contract worth $3 million from the then-Anaheim Angels and signed with Yomiuri. The Angels had expressed their continued interest in Uehara, as scouting director Eddie Bane had stated that acquiring either Uehara or Daisuke Matsuzaka was a top priority for the team. However, many other teams, including the Yankees, Dodgers, Red Sox, Mets, and Orioles, had shown interest in bidding for Uehara if he were to become available.

He was drafted with the first pick by the Yomiuri Giants in 1998.

In 1999, he had a successful rookie year with 15 consecutive wins that broke the all-time rookie record, claimed the Rookie of the Year, Eiji Sawamura Award, and led in wins, ERA, strikeouts and winning percentage. In the final game of the season against the Yakult Swallows, with the league standings already decided, Uehara was ordered to issue three intentional walks to the Swallows’ Roberto Petagine in order to give the Giants’ Hideki Matsui a chance to catch Petagine for the home run title. The competitive Uehara complied with the order but showed his bitterness on the mound, kicking the dirt repeatedly and even shedding tears after the third intentional walk.

In 2001, he finished with a 4.02 ERA, the highest of his career.

In 2002, he rebounded, leading the Central League in wins and collected his second Sawamura Award. After the 2002 season, he represented Japan in the Major League Baseball Japan All-Star Series and on November 11 became the first pitcher in over a year to strike out Barry Bonds three consecutive times in one game. This achievement raised his profile in American Major League Baseball.

He was a member of the Japanese national baseball team which competed in the 2004 Olympic Games in Athens. The team eventually won the bronze medal.

Uehara is a friend of former MLB pitcher Roger Clemens; they first met when Clemens visited Japan in 2004 MLB Japan All-Star Series. MLB.com featured a video in which Clemens gave Uehara a signed, game-used glove.

Uehara married his wife, Miho, in 2004. During his MLB career, Uehara lived with his family in Baltimore, where he said there were better educational opportunities for his son, Kazuma.

In 2006, he joined Team Japan for the World Baseball Classic and earned 2 wins, improving his unbeaten record in international competition (including amateur appearances) to 12 wins in 21 appearances. In the World Baseball Classic, Japan beat Cuba to win the championship; Uehara led the tournament with 16 strikeouts. He was a closer in 2007 Asian Baseball Championships, played in two games and earned his first international save against Korea.

Uehara asserted his preference in public to be transferred to a Major League Baseball team through the posting system. His efforts had been rebuffed by the Yomiuri Giants’ front office. He was expected to be eligible for free agency in 2007 (but that was postponed to 2008 due to injury). He became eligible for free agency in April 2008.

He was injured before the 2007 season which made him a late appearance, and in that season, he became a closer instead, recorded a 1.74 ERA with 4 wins, 3 losses, and 32 saves. Though showing a good ability both starting and closing, he returned as a starting pitcher in the 2008 season. He left the Giants after that season becoming a free agent and allowing him to play in Major League Baseball.

Uehara moved to another team in April 2008. He remained in the 39-out-of-77 men candidate list towards the Beijing Olympics in late June, and was selected to the final 24-men list in mid-July. He was expected to be a setup pitcher before the Olympic Games, but he appeared as a closer in his first appearance against Chinese Taipei, pitching a shutout inning without yielding a hit, as his team won 6–1. He earned his first Olympic save against Canada, holding a 1–0 victory two days later. Japan finished fourth in the Games. Uehara chose not to participate in the 2009 World Baseball Classic.

On January 13, 2009, Uehara signed a two-year, $10 million deal with the Baltimore Orioles. He started the 2009 season as the number two starter behind Jeremy Guthrie. Uehara made his big league debut on April 8 against the New York Yankees. Uehara earned the win, going five innings and allowing one run. His second outing resulted in a win against the Texas Rangers.

On September 10, 2009, it was announced that Uehara would be out for the remainder of the season. He would finish his injury-plagued 2009 campaign with a 2-4 record, 4.05 ERA, and 48 strikeouts in 66 2/3 innings in 12 starts. He started the 2010 season as a setup reliever in the bullpen and finished the season 1–2 with a 2.86 ERA, 55 strikeouts in 44 innings, and 13 saves.

On July 30, 2011, Uehara was traded to the Texas Rangers for Chris Davis and Tommy Hunter. The move reunited him with his old high school teammate Yoshinori Tateyama. After starting the season with superb numbers for the Orioles, his second half, with the Rangers, would prove to be a rough one. He was 1-2 with a 4.00 ERA after the trade. Matters would get worse in the postseason when he gave up three home runs in 1 1/3 innings to compile a 33.75 ERA before being left off the roster for the World Series due to his ineffectiveness. He would finish 2011 with a 2-3 record, 2.35 ERA, and 85 strikeouts in 65 innings after pitching for the two different teams.

In 2012, Uehara remained with the Rangers after his option vested. He would rebound with a successful campaign by keeping his ERA down to 1.75. However, he was limited to 36 innings in 37 games after spending some time on the disabled list with a strained lateral muscle.

On December 6, 2012, Uehara agreed to a one-year contract with the Boston Red Sox. Uehara transitioned his role from setup man to closer after season-ending injuries to Andrew Bailey and Joel Hanrahan.

Uehara’s 2013 season was one of the most dominant by any relief pitcher in baseball history. His 2013 WHIP of 0.57 in 74.1 innings set the record for a pitcher with 50 or more innings pitched. Between July 9 and September 17, Uehara retired 37 consecutive batters, exceeding the previous franchise record of 32, and nearing Bobby Jenks’ MLB record of 41 for consecutive outs by a reliever. Uehara finished the regular season with a 1.09 ERA, a 2.08 xFIP, and struck out 38.1% of batters he faced. He was ranked by Fangraphs as the number one reliever of 2013 in Wins Above Replacement.

On July 9, 2014, Uehara was named to his first career All-Star Game, replacing injured New York Yankees pitcher Masahiro Tanaka. He struggled near the end of the 2014 regular season and was removed from the closer role on September 5. He signed a two-year extension with the Red Sox on October 30, 2014, after finishing the regular season with a 6–5 record, 2.52 ERA, 80 strikeouts in 64 1/3 innings, and 26 saves in 31 opportunities as the Red Sox failed to defend its title by finishing with a subpar 71-91 record. Uehara returned to the closer position in the 2015 season, but on August 7, he suffered a season-ending injury when a batted ball struck his right wrist. He would prematurely end his 2015 campaign with a 2–4 record added by a 2.23 ERA, 47 strikeouts in 40 1/3 innings, and 25 saves in 27 attempts as the Red Sox failed to reach the .500 mark for the 2nd season in a row. In 2016, Uehara finished the regular season with a 2–3 record, a 3.45 ERA, 63 strikeouts in 47 innings, and 7 saves after spending some time on the disabled list with a pectoral strain. His team would make the postseason for the first time since the 2013 championship season. In the 2016 ALDS, Uehara pitched 2 games without allowing a run in 2 innings but the Red Sox got swept by the Cleveland Indians in 3 games.

On December 14, 2016, Uehara agreed to a one-year contract with the Chicago Cubs for $6 million.

On March 9, 2018, Uehara signed a one-year contract with the Yomiuri Giants, returning to Japan for the first time since 2008. He was selected to the 2018 NPB All-Star game [jp]. On July 20, 2018, Uehara became the second pitcher in history to have 100 wins, 100 holds, and 100 saves combined between NPB and MLB. On December 14, 2018, he re-signed with the Giants. In his final season with the Giants, he finished with a 4.00 ERA through nine innings, having struck out 10 batters.

After making nine appearances for Yomiuri in 2019, Uehara announced his retirement from professional baseball at the age of 44. Uehara finished his career having appeared in a combined 748 games across the MLB and the NPB, with a combined ERA of 2.93, 1,989 strikeouts, 134 wins, and 128 saves. He finished his career as the MLB’s all-time leader in strikeout-to-walk ratio among qualifying relievers, posting a 7.33 K/BB over his nine years in the MLB.