As a freshman in 2009, Rendon was named Baseball America’s Freshman of the Year, All-America, Freshman All-American, NCBWA’s District VII Player of the Year, NCAA All-Regional Team, Conference USA Player of the Year, All-Conference USA (first team), Conference USA All-Tournament Team, and MVP of the Silver Glove Series with cross-town rival, University of Houston. As a true freshman, he hit .388 with 20 home runs and 72 runs batted in, starting in all 61 of the Owls’ games. Rendon was also nominated for both the Dick Howser Trophy and the Golden Spikes Award in his first season at the college level. He led the conference in numerous offensive categories, including batting average, slugging percentage and home runs, setting a new Rice freshman record. He added 31 walks to his already gaudy offensive numbers, giving him a .496 on-base percentage. In addition to his batting prowess, he stole nine bases in eleven attempts, two away from leading the team, and showed defensive ability at third base as well; ending the year with a .945 fielding percentage. However, in Rice’s last game, in the Baton Rouge Super Regional, Rendon suffered an ankle injury that required surgery.

As a sophomore in 2010, he was the winner of the Dick Howser Trophy and was Baseball America’s College Player of the Year, becoming the first underclassman in a decade to win the award. Additionally, he was named the Rawlings Sporting Goods National Player of the Year, Conference USA Male Athlete of the Year, District VII Player of the Year, First Team All-American, All-south Region, Most Outstanding Player of the NCAA Austin Regional, All-Conference USA, All-Conference USA Tournament, and Conference USA Academic Honor Roll. He is also only the second player to be named Conference USA Player of the Year twice. He finished the season hitting .394 with 26 home runs and 85 runs batted in, again starting in every one of the Owls’ 63 games. Rendon’s 26 home runs were the second-highest single season total in school history; the only other Owl to hit more home runs in a year was Lance Berkman. In his sophomore campaign, Rendon hit more home runs (26) than he struck out (22), and his walks (65) nearly tripled his strikeout total. Again, Rendon flashed the leather, raising his fielding percentage to .978, making only four errors at third base. After his Rice season ended, Rendon was invited to represent his country playing on the international circuit for Team USA. He suffered another right ankle injury in the first game against South Korea.

Rendon was recalled by the Nationals on June 4, 2013, and replaced second baseman Danny Espinosa. Days later, on June 15, Rendon clubbed his first major league home run off Vinnie Pestano of the Cleveland Indians. The ninth-inning solo shot put the Nationals on top and they won 7–6.

After playing mostly second base the previous year, Rendon was moved back to his “natural position” as the Nationals’ third baseman in the 2014 season. The year would be a breakout one for Rendon, who led the National League in runs scored, with 111, while putting up a .287/.351/.473 slash line, hitting 21 home runs and stealing 17 bases over the course of the season. Rendon placed fifth in National League Most Valuable Player voting and was awarded a Silver Slugger for his performance as a top-hitting third baseman. He ranked second among National League position players in wins above replacement, just behind Andrew McCutchen of the Pittsburgh Pirates.

While Rendon emerged as a key cog in the Nationals’ offense during the season, his prowess in the playoffs was noteworthy as well, as he hit .368 in the 2014 National League Division Series against the San Francisco Giants.

Rendon sprained the medial collateral ligament in his left knee early during spring training in 2015, and then strained an oblique muscle while on a rehab assignment with the Class-AA Harrisburg Senators, being shut down on May 4. Rendon finally returned to major league action on June 4, 2015, but found himself moved back to second base, with the job of everyday third baseman being held down by new acquisition Yunel Escobar.

All in all, Rendon played in just 80 regular-season games in 2015 and put up a .264/.344/.363 slash line. His power was noticeably sapped following the oblique injury, as he hit just five home runs over the course of the season.

On September 6, 2016, Rendon hit his first career grand slam off Williams Perez, which provided the Nationals with a winning margin of victory over the division rival Atlanta Braves in the 9–7 contest.

On April 30, 2017, Rendon went six-for-six with three home runs and 10 RBI in a 23–5 win over the division rival New York Mets. He became the 13th major leaguer with 10 or more RBI in one game while setting a Nationals record. He became the third player in major league history attain both six hits and ten RBI in the same game, following Jim Bottomley (1924) and Walker Cooper (1949).

Despite leading all National League position players in wins above replacement during the first half of the season, Rendon was not selected to participate in the All-Star Game. He was one of the options in the “final vote” but lost out to Justin Turner of the Los Angeles Dodgers. Despite the All-Star snub, Rendon was named as Player of the Week in the National League on July 17, 2017, for the week abbreviated by the All-Star break. It was his first time so honored. Rendon hit .636 during the week with three home runs to earn the award. In 2017, he batted .301/.403/.533 with 25 home runs.

Rendon is frequently described by sports media as quiet and modest, qualities that when combined with his strong all-around offensive and defensive performance as an infielder for the Washington Nationals have led some, including 2016–17 Nationals manager Dusty Baker, to dub him one of the most “underrated” players in Major League Baseball. Explaining his philosophy on baseball to The Washington Post during spring training in 2017, Rendon said, “Obviously, I want to win, but at the same time, at the end of the day, it’s a game and that’s what I’m going to treat it as.” He claimed in a 2014 interview with the Post that he prefers watching the History channel to baseball, calling the sport “too long and boring”.

An avid basketball fan, Rendon follows the Houston Rockets, his hometown NBA team. He has maintained close ties to the Houston area. In the aftermath of Hurricane Harvey in August 2017, Rendon and then Nationals teammate Matt Albers, a fellow Houstonian, set up a YouCaring fundraiser page to raise money for donations to the Houston Food Bank.

In 2018, he batted .308 (4th in the NL)/.374/.535 (7th in the NL) with 24 home runs, and led the National League with 44 doubles.

On July 26, 2018, Rendon and wife Amanda welcomed their first child, Emma. Rendon took leave from the Nationals for several days to attend to the birth.

In 2019, he batted .319/.412/.598 with 34 home runs, led the NL with 44 doubles for the second year in a row, and led the majors in RBIs (126). He had the best walks/strikeouts ratio in the NL (0.93), and made contact with the highest percentage of pitches he swung at (88.3%) of all NL batters. He also hit for a 1.003 OPS in the postseason to help lead the Nationals to their first World Series championship. He hit key home runs in Games 6 and 7 of the World Series and his 8 RBI for the 2019 World Series were the most by a Nationals player. Following the 2019 World Series, Rendon and Nationals’ star pitcher Stephen Strasburg both entered free agency. Owner Mark Lerner had indicated that the team would not be able to afford to sign both players.

On December 11, 2019, Rendon agreed to a 7-year $245 million contract with the Los Angeles Angels, two days after Nationals signed Strasburg to a similar deal. He was formally introduced as an Angel on December 14, 2019. Rendon’s 6.7 Wins Above Replacement (WAR) in 2019 ranks only behind Mike Trout’s 8.4 WAR and above all Angels’ players except Trout from 2012 to 2019.

On July 28, 2020, Rendon made his Angels debut. In Rendon’s first 12 games with the Angels, he went 28 plate appearances without getting a hit. He ended the hitless streak on August 10, 2020, hitting a home run off of Sean Manaea of the Oakland Athletics. That same night, he recorded his 1000th MLB career hit.

In 2020 he batted .286/.418/.497 with 9 home runs and 31 RBIs, and tied for the AL lead by grounding into 10 double plays.