Nomo graduated from Seijo Industrial High School in Osaka where he grew to 188 centimetres (6 ft 2 in) and 91 kilograms (201 lb). However, he was not selected in the Nippon Professional Baseball draft due to issues with his control. Instead, in 1988, Nomo joined Shin-Nittetsu Sakai, an Industrial League team representing Nippon Steel’s branch in Sakai, Osaka. During this time, Nomo slept with a tennis ball taped between his fingers in order to perfect his forkball grip.

Nomo honed his forkball and his control while pitching in the Industrial League. At the 1988 Summer Olympics, Nomo played for the silver medal-winning Japanese baseball team and the Kintetsu Buffaloes drafted him in 1989. Nomo debuted with them in 1990 and was an immediate success, going 18–8 but more impressively striking out 287 hitters in just 235 innings. The strikeout numbers were attributed to his unorthodox wind-up, where he turned his back to the hitter, raised his pivot leg, and paused for a second before throwing. The delivery increased his pitch speed and made it more difficult for batters to spot the ball coming out of his hand. The windup gave him the nickname “Tornado.” Nomo won the Triple Crown that year.

In his first four seasons, Nomo was as consistent, and consistently good, as any pitcher in Japanese baseball, winning 17 or 18 games each year. His fifth season in 1994 was marred by a shoulder injury and netted him only eight wins. Nomo’s forkball became famous for being unpredictable for hitters and catchers alike.

Nomo had become one of the most popular baseball players in Japan but after the 1994 season, Nomo got into a contract dispute with team management. The Buffaloes rebuffed Nomo’s demands to have a contract agent and multi-year contract. Because he was drafted by Kintetsu, the Buffaloes retained exclusive rights to Nomo; however, Nomo’s agent, Don Nomura, found a loophole in the Japanese Uniform Players Contract to enable him to become a free agent. The “voluntary retirement clause” allowed a player who retired to play for whomever he wished after returning to active status. This led to him heading to the U.S., where in February 1995, the Los Angeles Dodgers signed him.

Nomo made his U.S. pro baseball debut with the Bakersfield Blaze on April 27, 1995, against the Rancho Cucamonga Quakes. Placed on a 90-pitch limit, and throwing mainly fastballs, Nomo pitched 5⅓ innings, taking the 2–1 loss against the Quakes. On May 2, after a month in the minors necessitated by a player’s strike, he became the first Japanese-born Major Leaguer to appear in a major league game since Masanori Murakami in 1965. He was also the first Japanese-born player to relocate permanently to the American major leagues, as Murakami played only two seasons with the San Francisco Giants and then returned to the Japanese major leagues for the remainder of his career. The pressure on Nomo would be tremendous, and Japanese media and fans appeared in large numbers in games he started. Nomo’s games were regularly broadcast live to Japan, despite the fact most people would be waking up when he started games.

The tornado delivery that baffled batters in Japan had the same effect on major league hitters, and he led the league in strikeouts in 1995 (while finishing second in walks) and was second with a 2.54 ERA. He struck out 11.101 batters per 9 innings to break Sandy Koufax’s single-season franchise record of 10.546 in 1962. He also started that year’s All-Star Game, striking out three of the six batters he faced. He topped out at 93 mph in that game. But he only barely won NL Rookie of the Year honors that year over future MVP Chipper Jones, as many voters felt that his Japanese success made him anything but a rookie, although he qualified by Major League rules. Nomo had another fine season in 1996 which was capped by a no-hitter thrown on September 17 in the unlikeliest of places, Denver’s Coors Field, a park notoriously known as being a hitters’ park because of its high elevation, semi-arid climate, and lack of foul territory. Nomo’s no-hitter remains as the only one in Coors Field, and was the last Dodger to throw a no-hitter until Josh Beckett completed one on May 25, 2014.

Nomo also found commercial success in America. Nomo had a signature sneaker, called the Air Max Nomo, produced by Nike in 1996. Also, he appeared on a Segata Sanshiro commercial for the Sega Saturn in 1997.

A song about Nomo, “There’s No One Like Nomo” performed by Jack Sheldon, written by Marvin Hamlisch and Alan and Marilyn Bergman, was released by GNP Crescendo Records (GNPD 1406) in 1996.

As batters caught on to his delivery, his effectiveness waned a bit in 1997, although he still went 14–12, joining Dwight Gooden as the only other pitcher to strike out at least 200 batters in each of his first three seasons.

Nomo pitched poorly in 1998, starting the season 2–7 and was dealt to the New York Mets. His performance did not improve and was released that season. In 1999, he signed with the Chicago Cubs and made three starts for their Triple-A minor league team before refusing to make further starts in the minors, and received a contract with the Milwaukee Brewers, where he went 12–8 with a 4.54 ERA. He reached the 1,000 strikeout mark in 1999, the third fastest in major league history. The Brewers waived him after contract issues and the Philadelphia Phillies claimed him, then granted him free agency only 24 hours later after more contract issues. Finally signed by the Detroit Tigers in 2000, he went 8–12 with a 4.74 ERA and was again released.

Nomo signed with the Boston Red Sox in 2001 and started the season in spectacular fashion, throwing his second no-hitter in his Sox debut, on April 4, against the Baltimore Orioles, walking three and striking out 11. This no-hitter was the first in the 10-year history of Oriole Park at Camden Yards and made Nomo the first Red Sox to pitch a no-hitter since Dave Morehead in 1965. Nomo also became just the fourth player in baseball history to have thrown a no-hitter in both leagues (joining Cy Young, Jim Bunning and Nolan Ryan. Randy Johnson would later join them, becoming the fifth player after throwing a perfect game in 2004). It is the earliest, calendar-wise, that a Major League Baseball no-hitter has been pitched. Nomo also led the league in strikeouts for the first time since his first season in MLB.

A free agent after the end of the year, Nomo returned to the Dodgers, in 2002. He ended up having his best season since 1996, posting a 16–6 record, 193 strikeouts, and 3.39 ERA. The following year, he had another strong season, going 16–13 with 177 K and a 3.09 ERA. During September 2003, however, he began to exhibit signs of injury and fatigue.

Nomo began to struggle again in 2004. After undergoing shoulder surgery in October 2003, he was benched after going 4–11 with an 8.25 ERA for the Dodgers (the worst ERA in the history of baseball for a player with at least 15 decisions in a season).

Nomo earned 123 wins in the Major Leagues and 78 in Japan, winning his 200th overall game on June 15, 2005. Nomo’s success helped inspire other stars from Japan such as Ichiro Suzuki, Hideki Matsui, and Daisuke Matsuzaka to come over to the States as well.

Before the start of spring training for 2005, he signed a $800,000 contract with the Tampa Bay Devil Rays. The contract also included a $700,000 incentive that kicked in if Nomo started 20 games. The stipulation was allegedly included because Devil Rays upper management was unsure if Nomo had fully recovered from his injury. After a poor start in which he posted a 7.24 ERA, he was released on July 25. Coincidentally or not, this was two days before he was slated to make his twentieth major league start. On July 27, Nomo was picked up off waivers by the New York Yankees, who signed him to a minor league contract, but never recalled him. Nomo was signed to a minor league contract by the Chicago White Sox during spring training in 2006 to play for the Triple-A Charlotte Knights of the International League, but the White Sox released him on June 7 of that year.

In 2007, Nomo signed on with the Leones del Caracas of the Venezuelan Winter League, managed by his former catcher, Carlos Hernández. His participation in the Venezuelan league was viewed as a first step toward an eventual Major League comeback. He made his debut on October 20, 2007, against Tiburones de La Guaira. Nomo pitched one inning, allowing one hit and no runs.

On January 4, 2008, Nomo signed a minor league contract for 2008 with the Kansas City Royals. If added to the roster Nomo would have received a $600,000 one-year contract and the chance to earn $100,000 in performance bonuses. On April 5, his contract was bought by the Royals and was added to the 25-man roster. On April 10, Nomo made his first major league appearance since 2005. He faced the New York Yankees in relief. He was brought in to start the seventh inning of a game while the Yankees were leading 4-1. Nomo loaded the bases, but was able to retire his native countryman, Hideki Matsui, to strand all three runners. However, he later surrendered back-to-back homers to Alex Rodriguez and Jorge Posada in the ninth inning. On April 20, Nomo was designated for assignment. The Royals released him on April 29, 2008. On July 17, 2008, Nomo officially announced his retirement from Major League Baseball.

Nomo was elected to the Japanese Baseball Hall of Fame in 2014, only the third ever to be selected in their first year of eligibility. At the time, he was also the youngest player ever elected to that Hall of Fame, although his record was broken in 2018 by Hideki Matsui.