At age 16, Altuve attended a Houston Astros’ tryout camp in Maracay. However, the team’s scouts declined to allow him to participate because they decided he was too short and they suspected that he had lied about his age. The next day, with encouragement from his father, Altuve returned to the camp and produced his birth certificate. Al Pedrique, then a special assistant for the Astros, asked Altuve, “Can you play?” Altuve looked him in the eye and said, “I’ll show you.” Pedrique championed him to the front office, convincing them that he had the talent and strength to eventually play in the major leagues. The club gave him an evaluation, and, after he impressed team officials, they signed him to a contract as an undrafted free agent on March 6, 2007, with a $15,000 (USD, $18,000 today) bonus.

After a strong 2007 season in the Venezuelan Summer League in which he hit .343, Altuve moved to the United States in 2008 and hit .284 in 40 games for the Greeneville Astros in the Rookie-level Appalachian League. He returned to Greeneville in 2009 and hit .324 with 21 stolen bases in just 45 games, earning him a spot on the league All-Star team, team most valuable player (MVP) honors, and a promotion to the Tri-City ValleyCats of the Class A-Short Season New York-Penn League for which he played in 21 games. He began 2010 with the Lexington Legends of the Class A South Atlantic League, hitting .308 with 39 steals and 11 home runs, earned a spot on the league all-star team, and then moved up to the Lancaster JetHawks in the Class A-Advanced California League and hit .276.

Returning to Lancaster for 2011, he hit .408 with 19 steals in 52 games. After being promoted to the Corpus Christi Hooks of the Class AA Texas League, he hit .361, giving him an overall line of .389 with 24 steals, 26 walks, and 40 strikeouts in 357 minor league at-bats that year. He was named the second baseman on Baseball America’s 2011 Minor League All Star Team as well as the Houston Astros Minor League Player of the Year. Altuve was called up to the major league club in mid-summer, bypassing Class AAA level.

The Astros promoted Altuve to the major leagues for the first time on July 19, 2011. He represented the Astros at the 2011 All-Star Futures Game. He was named the second baseman on Baseball America’s 2011 Minor League All-Star team. On July 27, 2011, Altuve tied Russ Johnson for the Astros record for most consecutive games with a hit to start a career with 7. On August 20, 2011, Altuve hit an inside-the-park home run, his first major league home-run. He became the first Astros player since Adam Everett in 2003 to hit an inside-the-park home run, the first Astros player to get his first major league home run on an inside-the-park home run since pitcher Butch Henry in 1992, and the first Astros player to lead off a game with an inside-the-park home run since Bill Doran in 1987. He batted .346 over his first 21 games before slumping a bit and ended the year with a .276 average. He also hit two home runs, stole seven bases, and posted a .358 slugging percentage in 221 at-bats.

On May 1, 2012, Altuve faced New York Mets reliever Jon Rauch, the tallest player in major league history at 6 feet 11 inches (2.11 m). The 18-inch (460 mm) height difference is believed to be the biggest between pitcher and batter with exception of a 1951 publicity stunt in which a 3-foot-7-inch (1.09 m) Eddie Gaedel had one plate appearance for the St. Louis Browns. Altuve was the Astros’ representative at the All-Star Game, played at Kauffman Stadium in Kansas City, Missouri. This was his first career selection.

On July 13, 2013, Altuve signed a four-year, $12.5 million extension that includes two club options for 2018 and 2019 worth $6 and $6.5 million respectively. The deal also included a $750,000 bonus to be received in 2013. At the time of the extension, Altuve was hitting .280 with 21 stolen bases, 15 doubles, and 28 RBI.

On June 29, 2014, Altuve stole two bases in a game against the Detroit Tigers. This made him the first MLB player since Ray Chapman in 1917 to steal two or more bases in four consecutive games. Altuve became the first MLB player since 1933 to have 130 hits and 40 stolen bases before the All-Star Break. Altuve was named to the 2014 All-Star Game. Coupled with his 2012 All-Star appearance in the Astros’ final season as a National League team, Altuve is the only player in Major League history to represent both the American and National Leagues in the All-Star Game while still being a member of the same team.

After the 2014 season, Altuve traveled to Japan to participate in the 2014 Major League Baseball Japan All-Star Series. He was named the GIBBY/This Year in Baseball Award winner as the Breakout Everyday Player of the Year. He won the first Silver Slugger Award of his career, as the top hitter among American League second basemen. He was also bestowed his first iteration of the Luis Aparicio Award, annually given to the Venezuelan judged to produce the best individual performance.

In 161 games, Altuve had an MLB-leading 216 hits, an AL-leading .338 batting average, 30 stolen bases. He also found a power surge with 42 doubles (the second most of his career and his third straight season with 40+ doubles), a career-high 24 home runs, and a career-high 96 RBI. This marked his second batting title, the last being in 2014.

On September 11, 2015, Altuve recorded his 800th career hit, surpassing Biggio for the fastest Astro player to reach 800 hits. In the final game of the season, Altuve went 3-for-5 to reach 200 hits for the second season in a row, which led the American League, while becoming both the first player in Astros history and Venezuelan to accumulate multiple 200-hit seasons. He also led the AL in stolen bases (38), and his .313 batting average was third best in the majors. He reached then-career highs with each of 15 home runs, .459 SLG, 86 runs scored, and 66 RBI. He led American League second basemen in fielding percentage (.993).

Altuve was awarded his first career Rawlings Gold Glove Award for second base on November 10, 2015. He also received his second consecutive Silver Slugger Award.

On November 1, 2016, Altuve’s wife Nina gave birth to their first child, a girl.

Prior to Game 2 of the World Series, Altuve was presented with the Hank Aaron Award, the first of his career, as the “most outstanding offensive performer” in the American League. It was the first time a Houston Astros player had won the prize. Next, he was named The Sporting News Major League Player of the Year for the second consecutive season, following Ted Williams (1941−42), Joe Morgan (1975−76), Albert Pujols (2008−09), and Miguel Cabrera (2012−13) as repeat winners in consecutive years of the honor given out since 1936. Other awards Altuve received in 2017 included Baseball America’s Major League Player of the Year award, becoming the first Venezuelan since Johan Santana in 2006 to receive the award bestowed since 1998. He was also the first second baseman and first Astro ever to win it. For the second consecutive season, he won the Players Choice Awards for Major League Player of the Year and AL Outstanding Player. He won his fourth consecutive and overall Silver Slugger Award at second base.

The Astros selected Altuve’s option for 2018, worth a reported $6 million, on November 3, 2017. On November 16, Altuve was conferred the AL Most Valuable Player Award, only the second Astro to win the award, following Jeff Bagwell in 1994. Altuve became the tenth second baseman to be granted MVP, and was the shortest player to win since Phil Rizzuto, also 5′ 6″, in 1950. Altuve became the first player since Buster Posey in 2012—and the eighth player overall—to win a batting title, MVP and World Series in the same season. On December 5, Altuve and Houston Texans defensive end J. J. Watt were named co-winners of the Sports Illustrated Sportsperson of the Year Award for his efforts in leading the Astros to their first World Series title and aiding in the recovery of the Greater Houston area in the aftermath of Hurricane Harvey. Altuve became the 18th Major League Baseball player to win the award in its 64-year history, and both the first Houston Astro and first Venezuelan player. He was also selected the 2017 Associated Press Male Athlete of the Year.

Prior to the 2018 season, Sports Illustrated ranked Altuve as the #2 player in baseball, trailing only Trout. On March 16, 2018, Altuve and the Astros agreed to a five-year, $151 million contract extension that would span the 2020–24 seasons. His current contract included a $6 million salary in 2018 and a $6.5 million team option in 2019. It was the largest contract in team history, and he became the sixth player to agree to a contract with an average annual value of $30 million per season or greater.

Altuve reached 1,000 games played in his career on April 17, 2018, versus the Seattle Mariners. He became the 20th player to appear in 1,000 games for the Astros. Over three games versus the Cleveland Indians spanning May 25–27, he realized a base hit in each of 10 consecutive at bats, breaking his own club record of eight which he had set the year prior. The streak included three doubles, one triple, and one home run.

On July 8, 2018, Altuve was selected as the starting second baseman for the American League in the All-Star Game, collecting the most votes of any player with 4,849,630 votes. It was his 6th All-Star selection overall and his 5th consecutive appearance and 4th straight start. On July 29, Altuve was placed on the disabled list for the first time in his MLB career due to right knee discomfort. Plagued with a right knee injury, the Astros announced that Altuve would serve as the designated hitter for the remainder of the season. In 137 games, Altuve finished with a .316 average, 13 home runs, and 61 RBI.

With the Astros finishing the year 103-59, the team clinched the AL West again, sweeping the Cleveland Indians in 3 games before eventually falling to the Red Sox in the ALCS. On October 19, 2018, Altuve officially underwent surgery to repair a patella avulsion fracture in his right knee. On November 8, Altuve was awarded his fifth career Silver Slugger Award and his fifth consecutive award. Having won his fifth award at second base, it tied him with Robinson Canó for most awards for an American League second baseman and second most all-time behind Ryne Sandberg.

In 2019, Altuve’s role in the 2017 World Series gained nationwide attention in the Houston Astros Sign Stealing Scandal. With regard to his accused role of wearing a wire and stealing signs, Altuve said, “I’m not going to say to you that it was good — it was wrong. We feel bad, we feel remorse, like I said, the impact on the fans, the impact on the game — we feel bad.”

On April 9, 2019, Altuve hit his 100th career home run off New York Yankees pitcher Jonathan Loáisiga. He became the 16th player in Astros history to reach 100 home runs. On April 12, Altuve connected for his second career grand slam, and first since 2014, in a 10–6 win over the Seattle Mariners. Altuve would hit another home run off of Félix Hernández the next night, making it the fifth consecutive game with a home run and sixth home run in that span. Altuve was the first Astro to hit a home run in five consecutive games since Morgan Ensberg’s franchise-record six consecutive games in 2006.

On July 2, 2019, Altuve doubled in the top of the seventh for his third of four hits in a 9–8 victory over the Colorado Rockies. His 142nd career three-hit game, Altuve passed Jeff Bagwell for second-most in Astros history, behind Craig Biggio (225). It was also Altuve’s second straight game with at least three hits, a 6–1 victory over the Seattle Mariners on June 30. He hit his third career grand slam and second of the season on July 14, yielding the Astros a franchise record-breaking ninth grand slam in a single season.

Altuve continued his hot hitting in October. During the ALDS Altuve hit 3 home runs en route to a 3-2 series victory over the Tampa Bay Rays. With his 3rd home run of the series in Game 5, Altuve hit his 11th career postseason home run, the most by any second baseman in baseball history and drew him into a tie with George Springer for most postseason home runs by a Houston Astros player. Altuve’s ninth-inning walk-off home run off Aroldis Chapman in Game 6 of the ALCS sent Houston back to the World Series. Altuve received the ALCS MVP award for his performance in the series, batting .348 with 2 home runs, 3 RBIs, 6 runs scored, and a 1.097 OPS. He also set the record for the most career postseason homers by a second baseman (13). He hit .303 with no home runs and one RBI in the 2019 World Series, which the Astros lost to the Washington Nationals.