A right-handed batter, Fregosi is one of many notable alumni of Junípero Serra High School of San Mateo, California, and was signed by the Boston Red Sox in 1960. The same year he was selected by the Angels in the 1960 MLB Expansion Draft, and made his debut in September 1961. After hitting .291 as a reserve in 1962, he batted .287 – ninth in the AL – in his first full season in 1963, and was second in the league in triples and fifth in hits. He made his first All-Star squad in 1964, batting .277. From 1964 to mid-1969, he teamed with second basemanBobby Knoop to form one of the game's top double play combinations; with Knoop winning Gold Gloves from 1966–68, the two became only the third middle infield combination to win the honor in the same season (1967). On July 28, 1964, he became the first Angel to hit for the cycle (and the only man to do so at Dodger Stadium until Orlando Hudson accomplished the feat in 2009), and he did so again on May 20, 1968 but this one was an unnatural cycle. Fregosi continued to turn out solid years, particularly in 1967 when he batted .290 (seventh in the AL) and won his only Gold Glove, finishing seventh in the MVP voting. He became regarded as the league's top-hitting shortstop, leading the AL in triples (13) in 1968, and was named an All-Star every season from 1966 to 1970. But he was sidelined in 1971 when a tumor was discovered in his foot. The Angels became uncertain of Fregosi's future, and on December 10 traded him to the New York Mets in the same deal that brought pitcherNolan Ryan to California. (Fregosi would later manage Ryan in 1978 and 1979, Ryan's last two years as an Angel.)
Sidelined by several injuries including a broken thumb in 1972, Fregosi struggled with the Mets, where he played mainly at third base, and was sold to the Texas Rangers in the 1973 mid-season. After five years as a backup for the Rangers (1973–77), during which he played primarily as a first baseman, he was sent to the Pittsburgh Pirates in June 1977. When the Angels expressed interest in naming him as their manager in 1978, the Pirates released him to pursue the opportunity.
In becoming the Angels' manager at age 36, Fregosi was presented with a solid team nucleus of Ryan, Baylor, Downing, Bobby Grich, Carney Lansford, Frank Tanana and longtime owner Gene Autry, compiling a record of 62-55 in 117 games, and tying for second with Texas behind the Kansas City Royals. In 1979, with the addition of Rod Carew, he led the Angels to an 88-74 record, surprising the Royals and winning the first title in the club's 19-year existence. But they didn't have enough to get by the Baltimore Orioles in the 1979 American League Championship Series, losing Game 1 in 10 innings and dropping a 9-8 slugfest in Game 2; the Angels captured a 4-3 win in Game 3, scoring twice in the bottom of the ninth on an error and a Larry Harlow double, but were knocked out in an 8-0 Game 4 loss. After Ryan's departure to the Houston Astros at the end of the season, the team's pitching faltered in 1980, and the club dropped back into sixth place in their division; Fregosi was replaced in the first half of the 1981 season.
From the Angels, Fregosi managed the Louisville Redbirds of the American Association for three seasons. Louisville won the league championship in Fregosi's first season in 1983, and lost the league championship in the playoffs. In Fregosi's second season, Louisville tied for fourth place in the regular season but won the 1984 league championship. In 1985 Fregosi's Louisville team finished the season in first place and won the league championship in the playoffs also.
Fregosi got a new chance in the major leagues with the Chicago White Sox in 1986. Fregosi managed the team for three seasons, in each of which the White Sox finished in fifth place in the American League West. Fregosi was released at the end of the 1988 season.
Despite the World Series run, Fregosi was often the target of criticism by the Philadelphia sports media. One general criticism of Fregosi was that he was a manager who relied on veteran players and was unable to develop younger players. He was ultimately released by the Phillies in 1996 after posting a series of dismal post-1993 seasons.
Fregosi was hired away from the San Francisco Giants (where he had been serving as a special assistant) as the new manager for the Blue Jays in 1999, and was replaced after the 2000 season despite the fact that the team finished in third place and above .500 in each of his two years in Toronto. As a manager, he had a record of 1028-1095 in 15 seasons.
At the end of 2004, when the Phillies were looking for a manager to replace Larry Bowa, Fregosi surfaced as a candidate for the job. The job ended up going to Charlie Manuel.
Fregosi's number "11" was retired by the Angels in 1998.
Fregosi delivered a eulogy at the March 2007 funeral of longtime friend and former Phillies coach John Vukovich.