Rendon is the second son of Rene and Bridget Rendon. His parents say Rendon started playing baseball at a very early age; hitting pine cones with sticks as early as the age of three. Rendon grew up on the southwest side of Houston and excelled academically and in sports. He was a star basketball player, track athlete and baseball player at Hodges Bend Middle School. For the first two and a half years of high school, Rendon attended George Bush High School, before transferring to Lamar High School. As a senior he was a first team 5A all-state shortstop and an All-Greater Houston selection by the Houston Chronicle after he hit .570 with eight home runs, 17 doubles, 56 Runs batted in, 56 runs scored and 13 stolen bases. Out of high school, Rendon was drafted in the 27th round of the Major League Baseball Draft by the Atlanta Braves. He turned down their signing bonus to play for Rice University and head coach Wayne Graham.
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 freshmen record at 20. 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 9 bases in 11 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 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 the 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 strike out total. Again, Rendon flashed the leather, raising his fielding percentage to an unprecedented .978, making only four errors all season 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, and replaced second baseman Danny Espinosa. He finished the season with the major league team, batting .265 with 7 home runs, 35 runs batted in, and 1 stolen base in 98 total games in the majors.
Rendon posted an all-star quality first half. While switching between third base and second base, by the All Star break Rendon was hitting .284/.340/.491 with 13 homers, 62 runs and 52 RBI. He ranks ninth among all National League position players in wins above replacement (per FanGraphs) with 3.3. He came in fourth in All Star voting for third base.