Rodney was signed by the Detroit Tigers as an amateur free agent in 1997. He spent 1999–2003 in the minor leagues, moving from the Gulf Coast League to the International League. Rodney underwent Tommy John surgery following the 2003 season (which he spent in the minor leagues). He spent the 2004 season recovering and failed to make the Tigers opening day roster after 2005 spring training.

In 2005, Rodney became the Tigers closer after Troy Percival went down with an arm injury and his replacement, Kyle Farnsworth, was traded at mid-season to the Atlanta Braves. He was called up from Toledo after Farnsworth was traded, then settled into the closer role, earning nine saves in 39 total appearances, during which he racked up a 2.86 earned run average.

On July 3, 2006, at McAfee Coliseum in Oakland, California, Justin Verlander, Joel Zumaya, and Rodney each threw multiple fastballs clocked in at over 100 mph, becoming the first time in MLB history that three pitchers on the same team had done so during one game. Rodney was part of the 2006 World Series roster—Rodney’s first World Series appearance. The Tigers would end up losing the World Series to the St. Louis Cardinals.

Rodney started 2008 on the disabled list with shoulder tendinitis. He re-joined the big league club in mid-June. On July 27, Rodney was announced as the Tigers’ new closer, replacing Todd Jones. Despite a 4.40 ERA in the 2009 season, Rodney was successful in save situations, converting 37 of his 38 save opportunities.

Following the 2009 season, the Tigers offered arbitration to Rodney, which he rejected to pursue a multi-year deal. He was expected to be one of the more valuable closers on the market because as a “Type B” free agent, he would only cost teams a supplementary draft pick. His 1.40 ground ball-to-fly ball ratio ranked first that year among free-agent closers. Originally, the Baltimore Orioles and Philadelphia Phillies were rumored to be interested in signing Rodney. The Los Angeles Angels of Anaheim were also reported to be in serious discussions with his agent.

On December 24, 2009, Rodney signed a two-year, $11 million contract with the Los Angeles Angels of Anaheim. Although he closed for the Detroit Tigers in 2009, “Rodney is expected to share setup duties with Scot Shields and Kevin Jepsen and close on a fill-in basis when Brian Fuentes is down”, the Los Angeles Times reported. Rodney stated, “I think I’m a different pitcher in save situations”, referring to his lower ERA in save situations. He filled in April for Angels’ closer Brian Fuentes when he went on the disabled list with a strained back.

Three days after the Angels traded Fuentes to the Minnesota Twins on August 27, 2010, it was officially announced that Rodney would be the new closer by manager Mike Scioscia. On April 5, 2011, Rodney was replaced by Jordan Walden as the full-time closer.

Rodney signed a $1.75 million deal with the Tampa Bay Rays for the 2012 season. While Kyle Farnsworth was on the 60-day disabled list, Rodney performed in the closer role and maintained that role after Farnsworth returned from his injury. He was selected on July 6 to participate in his first ever All-Star Game. On that date, he had converted 24 of 25 save opportunities. At the end of the 2012 season, Rodney had converted 48 saves, the second most that season behind Jim Johnson of the Baltimore Orioles. His 0.60 earned run average for the season was the lowest by a qualifying relief pitcher in major league history. On October 19, 2012, Rodney was named the AL Comeback Player of the Year and the Delivery Man of the Year During his time with the Rays, Rodney mimed shooting an arrow to high center field after converting a save as his celebration move.

Rodney is also known for celebrating a save by pretending to shoot a bow and arrow toward the sky, usually at a point high over center field. He started the routine while with the Rays after saving a 1–0 ballgame on April 16, 2012 against their rival, the Boston Red Sox. It became his tradition after successfully saving each game that season, and soon involved his Rays teammates. The infielders would approach the mound to watch Rodney shoot the arrow, and first baseman Carlos Pena would ask him where it had gone, with both theatrically pointing off into the distance as if following its flight.

Rodney has primarily been a fastball-changeup pitcher. He throws both a two-seam sinking fastball averaging 95–96 MPH, and a four seam fastball averaging 96–97 MPH. His fastball has been thrown as high as 101.5 MPH, most recently in 2013. His main offspeed pitch is a changeup at about 84 MPH. Opponents have hit the changeup at just a .179 clip over Rodney’s career.

On February 6, 2014, Rodney signed a 2-year, $14 million contract with the Seattle Mariners. After leading the American League in saves in the first half of the season, Rodney was named as a late addition to the AL All-Star team, taking the spot of David Price (who had pitched the Sunday before the game and thus could not pitch in the actual All-Star Game). Rodney finished the 2014 season with an MLB-best 48 saves, which also topped Kazuhiro Sasaki’s 45 saves for a new Mariners franchise record.

Rodney was unable to continue his success into 2015, and the Mariners designated him for assignment on August 22. In 2015 with Seattle, he was 5–5 with a 5.68 ERA.

Rodney was traded to the Chicago Cubs for cash considerations on August 27, 2015. He wore jersey #57, the first time in his career in which he wore a number other than 56. His Cubs debut came on August 28 at Dodger Stadium, where he already blew a save during the season. He pitched a scoreless eighth despite hitting a batter and throwing a wild pitch. With the Cubs in 2015, Rodney allowed only one earned run in 12 innings.

On February 4, 2016, Rodney signed a one-year, $2 million contract with the San Diego Padres. On April 11, 2016, Rodney pitched a scoreless ninth inning to record his first save as a Padre in a win over the Philadelphia Phillies.

Despite going 17-for-17 in save situations and posting a 0.31 ERA for the Padres, Rodney was traded to the Miami Marlins on June 30, 2016 for Chris Paddack. He was 2–3 with Miami and pitched to a 5.89 ERA.

On December 9, 2016, Rodney signed a one-year, $2.75 million contract with the Arizona Diamondbacks. Rodney recorded his first win for the Diamondbacks on opening day and his first save in his next appearance on April 5, 2017. On June 7, Rodney became the 42nd pitcher all-time to finish 500 career games. On September 22, Rodney became the 28th pitcher all-time to record 300 career saves in a victory over the Miami Marlins.

Rodney is known for wearing his cap tilted at an angle toward the left side of his head. He said in 2016 that it came about as a tribute to his father, Ulise Rodney, who was a fisherman. Ulise also wore his cap tilted to the side because that was the side the sun hit his face. Rodney also said the tilted cap could be confusing for both hitters and baserunners. “The hitter looks for your eyes. It’s like a dog. When you go somewhere, the first thing (a dog) looks at is your eyes and how you move.”

On December 15, 2017, Rodney signed a one-year, $4.5 million contract with the Minnesota Twins. The contract included incentives that could increase the amount to $6 million, as well as a 2019 team option.

On August 9, 2018, the Twins traded Rodney to the Oakland Athletics in exchange for minor league pitcher Dakota Chalmers. In 22 games for the A’s, Rodney served as a setup man. He pitched to a 3.92 ERA in 20 ⁄3 innings. In 2018 he was the third-oldest player in the American League.

On June 25, 2018, Rodney became a naturalized United States citizen. Rodney lives in Pembroke Pines, Florida.

On May 25, 2019, Rodney was designated for assignment by the Oakland A’s. The A’s released Rodney three days later. He had a 9.42 ERA in 17 appearances.

On June 1, 2019, Rodney signed a minor league contract with the Washington Nationals. On June 25, he was called up to the major leagues.

His combined record in 2019 was 0–5 with two saves and a 5.66 ERA in 47.2 innings. He was the second-oldest player in the major leagues, behind Ichiro Suzuki. Rodney became the fourth player to appear in all rounds of the postseason (Wild Card, Division Series, Champion Series, and World Series) in both the AL and NL. He had 6 postseason appearances, 3 of which came in the World Series.

On July 18, 2020, Rodney signed with the Sugar Land Skeeters of the Atlantic League of Professional Baseball.

On July 31, 2020, the Astros signed Rodney to a minor league deal. Rodney was released by the Astros on September 2, 2020.