Vizquel started his career with the Leones del Caracas of the Venezuelan Winter League together with Tony Armas, Bo Díaz and Andrés Galarraga. He learned to switch hit from Bill Plummer who managed Vizquel with the Leones del Caracas, in 1986-87 and 1988-89, and coached and managed the Mariners. Originally signed by the Mariners as a non-drafted free agent in 1984, Vizquel made his Major League debut on April 3, 1989. Batting ninth in the lineup, he went 0-for-3 while making five assists, a double play and an error in a 3-2 loss to the Oakland Athletics. Three nights later, he collected his first career hit in the third inning against Storm Davis with a single, later scoring on a Darnell Coles double, although the Mariners lost 11-3 to the Athletics.

Vizquel married Nicole, a Seattle native, in 1992. They later divorced, and Vizquel married Blanca Garcia in July 2014.

Vizquel won nine consecutive Gold Gloves with the Mariners and Indians, starting with his first in 1993 with Seattle and continuing until 2001. Alex Rodriguez broke Vizquel’s streak and won the award in 2002. Vizquel won two additional Gold Gloves in 2005 and 2006 with the San Francisco Giants.

At the end of the 1993 season, Vizquel was traded by the Mariners to the Indians for Félix Fermín, Reggie Jefferson, and cash. During Vizquel’s career in Cleveland, the Indians made it to the World Series twice, losing to the Atlanta Braves in 1995 and to the Florida Marlins in 1997. Vizquel is a lifetime .250 hitter in 57 postseason games.

In 1999, Vizquel hit over .300 and scored 100 runs for the first time in his career, finishing the season with a .333 batting average and 112 runs scored for an Indians team that scored a league-leading 1,009 runs. Vizquel hit second in the line-up between lead-off man Kenny Lofton and third-place hitter Alomar in the most productive offensive line-up in Cleveland baseball history. This line-up also included power hitters Jim Thome and Manny Ramirez.

On August 5, 2001, Vizquel hit a three-run triple in the ninth inning against the Seattle Mariners to tie the game 14–14, capping a comeback from a 14–2 deficit. The Indians went on to win 15–14 in 11 innings, tying the record for the largest comeback win in history. Vizquel reached career highs in 2002 hitting 14 homers and 72 RBI, but his success was interrupted by the need for surgery on his right knee. He tied the 2002 All-Star Game 7–7 with an RBI triple in the eighth inning. As a result of his knee injury in 2002 and a follow-up operation, he appeared in only 64 games in 2003. In a game on May 27, 2003, Vizquel had a straight steal of home against the Detroit Tigers. He caught Tigers pitcher Steve Avery by surprise and made it home without a throw. Vizquel returned in 2004 to hit .291 in 148 games. At the end of the season, Vizquel was signed by the Giants as a free agent.

His 2002 autobiography, Omar!: My Life on and Off the Field, which he co-wrote with Bob Dyer, spent four weeks on the New York Times Best Seller List. It was released in paperback in 2003.

A long-running and well-publicized feud erupted between Vizquel and former teammate and friend José Mesa. In 2002, following the publication of his autobiography, Omar! My Life On and Off the Field, Vizquel criticized Mesa’s performance in Game 7 of the 1997 World Series:

On June 12, 2002, Mesa hit Vizquel with a pitch in the ninth inning. Mesa was not ejected and finished the game. They did not face each other again until 2006; by then, Vizquel was with the San Francisco Giants and Mesa was playing for the Colorado Rockies. When Vizquel came to bat against Mesa in Denver on April 22, Mesa hit him again. Meeting three more times in 2006, however, Vizquel escaped being hit by his former teammate, with two groundouts and an RBI single. Vizquel batted .333 (7-for-21) against Mesa before Mesa’s retirement in 2007.

Vizquel was Greg Maddux’s 3000th strikeout victim on July 26, 2005.

On June 23, 2007 the Hispanic Heritage Baseball Museum Hall of Fame inducted Vizquel, along with former Giants outfielder Matty Alou, into its Hall of Fame during an on-field, pre-game ceremony. For the 13th and final time, Vizquel finished in the top ten in sacrifice hits, having 14 to finish 2nd along with John Maine behind Juan Pierre.

Vizquel underwent arthroscopic knee surgery on February 27, 2008. He started the 2008 season on the disabled list and played in his first game on May 10. Vizquel stole home for the second time in his career against Oakland Athletics pitcher Greg Smith on June 13.

On January 21, 2009, Vizquel signed a minor league contract with the Texas Rangers and made the team’s major league roster. He served mainly as a backup middle infielder. In 62 games with the Rangers, he had 47 hits, 17 runs, 14 RBIs with a .266 batting average and a .660 OPS to go with 27 strikeouts and 13 walks. In each of the three positions (shortstop, third base, second base) he played with the team, he made no errors. He played 27 games at shortstop for 196.2 innings, making 32 putouts and 76 assists with 22 double plays turned; he appeared in 20 games at third base for 101 innings, having five putouts and 22 assists, while making 23 putouts and 49 assists at second base.

On November 23, 2009, Vizquel agreed to a one-year contract with the Chicago White Sox worth $1.4 million. After making the deal official, former shortstop and White Sox legend Luis Aparicio asked that his number 11 be temporarily “unretired” for Vizquel during the 2010 season, mostly due to the fact that White Sox manager Ozzie Guillén — like Vizquel and Aparicio, a Venezuelan shortstop — had rights to #13, the number Vizquel has worn through his career.

On May 25, 2010, Vizquel became the shortstop with the third most hits all time, behind Derek Jeter and Honus Wagner. On June 25, he hit his first home run of 2010, putting him on the short list of players who have hit home runs in four different decades (with Ted Williams, Willie McCovey, and Rickey Henderson). On November 2, 2010, Vizquel signed a one-year deal to remain in Chicago. On April 3, 2011, Vizquel got a single for his 2,800th career hit. Despite being well into his forties, Vizquel was still regarded as one of the better defensive shortstops in the game and seen by his former White Sox teammates as one of the most physically fit.

In the final game of the 2012 season, Brett Lawrie wore a #17 jersey as opposed to his usual #13. This allowed Vizquel to wear #13 (the number he wore through most of his career) when he played his final game on October 3, 2012. Vizquel went 1 for 3, hitting a single in his last at bat, the 2,877th hit of his career moving him ahead of Mel Ott for 40th position on the all-time hits list. Vizquel retired after the season and was the last position player born in the 1960s, as well as the last to play in the 1980s, to retire.

On January 30, 2013, Vizquel was hired by the Los Angeles Angels of Anaheim to become a co-infield coach with Bobby Knoop, to replace Dick Schofield, whose contract was not renewed for 2013.

On November 18, 2013, the Detroit Tigers named Vizquel as their new first-base coach, replacing Rafael Belliard. Under manager Brad Ausmus, Vizquel also served as the Tigers infield and baserunning instructor. Following the dismissal of Ausmus after the 2017 season, Vizquel interviewed for the vacant manager’s position, but was passed over in favor of Ron Gardenhire.

On November 2017 Vizquel returned to the White Sox organization to manage their Class A-Advanced team, the Winston-Salem Dash. In December 2018 Vizquel was promoted to manage the White Sox’ Class AA team, the Birmingham Barons.

On December 2, 2019, Vizquel was named as the new manager for the Toros de Tijuana of the Mexican League for the 2020 season.