In 1977, Valenzuela began his professional baseball career when he signed with the Mayos de Navojoa. A year later, he was sent to the Guanajuato Tuzos of the Mexican Central League, posting a 5–6 record with a 2.23 ERA. The following year, the Mexican Central League was absorbed into the expanded Liga Mexicana de Beisbol (Mexican Baseball League), automatically elevating then 18-year-old Valenzuela to the Triple-A level. Pitching for the Leones de Yucatán (Yucatán Lions) that year, Valenzuela went 10–12 with a 2.49 ERA and 141 strikeouts.

A number of MLB teams scouted Valenzuela during this time. Los Angeles Dodgers scout Mike Brito had gone to a game in Mexico to evaluate a shortstop named Ali Uscanga. Valenzuela threw three balls to Uscanga to fall behind in the count and then threw three straight strikes to strike out the batter. Brito said later that at that point, he “forgot all about the shortstop.” The Dodgers finally gambled on the young lefty, buying out his Liga contract on July 6, 1979, for $120,000.

After acquiring Valenzuela in the summer of 1979, the Dodgers assigned him to the Lodi Dodgers of the High-A level California League where he posted a 1–2 record and a 1.13 earned run average (ERA) in limited action. The Dodgers felt that Valenzuela needed to learn to throw an off-speed pitch, so they had Dodgers pitcher Bobby Castillo teach him to throw the screwball before the 1980 season. In 1980 Valenzuela was promoted to the Double-A level San Antonio Dodgers. There Valenzuela led the Texas League with 162 strikeouts, finishing the season with a 13–9 win-loss record and a 3.10 ERA.

Valenzuela was called up to the Los Angeles Dodgers bullpen in September 1980. In the last month of the season, Valenzuela helped the Dodgers to a tie with the Houston Astros for the National League Western Division lead, pitching 17⁄3 scoreless innings of relief over the course of ten games, during which he earned two wins and a save. However, the Dodgers then lost a one-game playoff—and thus, the division championship—to the Astros.

Fernando Valenzuela, the youngest of twelve children, was born in Etchohuaquila, a small town within the municipality of Navojoa in the state of Sonora, Mexico. His birth date is officially listed as November 1, 1960, but during his rookie season in 1981, several commentators questioned his age, guessing him to be significantly older than twenty.

Valenzuela was considered an atypically good hitter for a pitcher. His best year at the plate was 1990—his last year with the Dodgers—when he hit .304 with 5 doubles, 1 home run, and 11 RBI in 69 at-bats. That gave him a 101 OPS+, meaning Valenzuela ranked just above average among all National League hitters that year, including non-pitchers. With 187 hits in 936 career at-bats—roughly two full seasons worth of at-bats for a full-time position player—his career batting average was .200, with 10 home runs, 26 doubles, and 84 RBI. Valenzuela was even used on occasion as a pinch-hitter, batting .368 (7-for-19) in such situations. Twice while with the Dodgers, Valenzuela was called upon to play outfield and first base in marathon extra-inning games in which he did not pitch. He won the Silver Slugger award for pitchers in 1981 and 1983.

In 1981, Valenzuela married Linda Burgos, a schoolteacher from Mexico. Early in his career, Valenzuela and his family spent offseasons between the Mexican cities of Etchohuaquila and Mérida. The couple have four children. One of Valenzuela’s sons, Fernando, Jr., played in the San Diego Padres and Chicago White Sox organizations as a first baseman. Since 2006, Fernando Jr. has played minor league baseball in Mexico or in independent leagues.

Following his outstanding debut, Valenzuela, nicknamed “El Toro” (the Bull) by fans, settled down into a number of years as a workhorse starter and one of the league’s best pitchers. He had one of his best seasons in 1986, when he finished 21–11 with a 3.14 ERA and led the league in wins, complete games and innings pitched. He lost a narrow vote for the Cy Young Award to the Astros’ Mike Scott.

At the 1986 All-Star Game, Valenzuela made history by striking out five consecutive American League batters, tying a record set by fellow left-handed screwballer Carl Hubbell in the 1934 contest.

In 1987 his performance declined; he earned a 14–14 win-loss record with a 3.98 ERA. In 1988, a year in which the Dodgers won the World Series, he won just five games and missed much of the season, despite not being on the postseason roster, he still earned a second World Series ring. He improved slightly in 1989 and went 10–13; he posted a 13–13 record in 1990. He had one last great moment on June 29, 1990, when he threw a 6–0 no-hitter against the St. Louis Cardinals just hours after the Oakland Athletics’ Dave Stewart had thrown one against the Toronto Blue Jays. According to teammate Mike Scioscia, Fernando and many Dodger players watched Stewart, who was a former Dodgers player, throw the no-hitter on TV. Afterward, before his game, Fernando said to his teammates, “You just saw a no-hitter on TV. Now you will see one in person.”

After pitching ineffectively in spring training in 1991, Valenzuela was released by the Dodgers. At the time of Valenzuela’s release, several Dodgers leaders, including Tommy Lasorda, Fred Claire, and Peter O’Malley, praised Valenzuela for creating exciting memories over several seasons and they indicated that it was a difficult decision to release him.

An abortive attempt at a comeback with the California Angels failed later that summer. Valenzuela signed with the Detroit Tigers in the spring of 1992, but he never played for the team, and was out of the Majors in 1992, with his contract being purchased by Jalisco of the Mexican League that summer. He pitched and played some first base when he wasn’t on the mound before making another brief comeback in 1993 with the Baltimore Orioles.

Jumping between the big leagues and Mexico for the next few seasons, he put together one more solid big-league season in 1996 for the San Diego Padres, going 13–8 with a 3.62 ERA. He retired a year later with a final record of 173–153 and a 3.54 ERA as a member of the St. Louis Cardinals.

The Los Angeles Dodgers invited him to spring training in 1999, but he declined the offer.

In 2003, Valenzuela returned to the Dodgers organization as the Spanish-language radio color commentator for National League West games, joining Jaime Jarrín and Pepe Ýñiguez in the Spanish-language booth. In 2015, he was switched to the color commentator job on the Spanish-language feed of SportsNet LA.

Valenzuela was inducted into the Hispanic Heritage Baseball Museum Hall of Fame on August 23, 2003, in a pregame on the field ceremony at Dodger Stadium. In 2005, he was named one of three starting pitchers on MLB’s Latino Legends Team. In 2013, he was enshrined into the Caribbean Baseball Hall of Fame. Valenzuela was inducted into the Baseball Reliquary’s Shrine of the Eternals in 2006.

On June 29, 2004, Valenzuela announced he would return to the mound in the Liga Mexicana del Pacífico (the Mexican Pacific Coast League) to play for Los Aguilas de Mexicali in October; he was nearly 44 years old at the time. He pitched again in the Mexican winter league during the 2005–06 season. On December 20, 2006, in Mexicali, BC, Mexico, Fernando Valenzuela was the starting pitcher for Los Aguilas de Mexicali in the last professional game of his career.

On October 26, 2010, ESPN broadcast a documentary commemorating Valenzuela’s arrival with the Dodgers titled Fernando Nation as part of their 30 for 30 documentary series.

Valenzuela became a U.S. citizen on July 22, 2015, at a ceremony in downtown Los Angeles. He has participated in two Tournament of Roses Parades—in 1983 aboard the float from the Government of Mexico and in 2008 aboard the Los Angeles Dodgers’ float. In 1981, Valenzuela participated in the East Los Angeles Christmas Parade as Grand Marshal.

He purchased the Mexican League team Tigres de Quintana Roo in 2017.

On October 25, 2017, Valenzuela threw the first pitch at game 2 of the 2017 World Series at Dodger Stadium, introduced by recently retired announcer Vin Scully, and joined by Steve Yeager.

The Mexican Baseball League commemorated the great legacy of Fernando Valenzuela on 6 July 2019 and retired his jersey number #34 from the entire league.