After playing for three years in the minor leagues, Sanguillen joined the Pirates in 1967, playing in 30 games. He played another season in the minor leagues in 1968, before returning to the Major Leagues in 1969. He replaced Jerry May as the Pirates starting catcher and posted a .303 batting average. He solidified his reputation as one of the top hitting catchers in baseball by hitting for a .325 batting average in 1970, finishing third in the National League batting championship behind Rico Carty and Joe Torre.

In a 13-year career, Sanguillen played in 1,448 games, accumulating 1,500 hits in 5,062 at bats for a .296 career batting average, along with 65 home runs and 585 runs batted in. He ended his career with a .986 fielding percentage. Sanguillen was the Pirates’ catcher on September 20, 1969 when Bob Moose pitched a no-hitter. Along with his three All-Star Game appearances, he was a member of two world championship winning teams in 1971 and 1979, and finished in eighth place in the 1971 Most Valuable Player Award balloting results. Sanguillen edged out Johnny Bench on The Sporting News National League All-Star Team in 1971, the only time between 1967 and 1975 that Bench was not selected.

Sanguillen was a valuable member of the world champion 1971 Pirates. He had his best year in terms of offensive production by hitting for a .319 batting average, while hitting 7 home runs and 81 runs batted in. He also had his best year defensively, finishing third among National League catchers in games caught (135), second in base runners caught stealing (37), caught stealing percentage (51.4%), fielding percentage (.994) and first in assists (72). The Pirates won the National League Eastern Division pennant by 7 games over the St. Louis Cardinals, then defeated the San Francisco Giants in the 1971 National League Championship Series, before winning the World Series against the Baltimore Orioles. In the seven-game series, Sanguillen had a .379 batting average with 11 hits, second only to the 12 hits by Roberto Clemente.

Sanguillen was a close friend of his teammate Roberto Clemente. In 1972, Sanguillen, who had been playing winter baseball with the San Juan Senators, spoke to Clemente about accompanying him on a relief mission to Nicaragua. Sanguillen missed the plane because he had misplaced his car keys; he was devastated when he learned that the plane had crashed, killing Clemente. Against the advice of Pirates General Manager Joe Brown, Sanguillen insisted on helping to recover the bodies of those who died in the crash. The sight of many sharks swimming in the water did not stop Sanguillen. As Pirates teammate Steve Blass told The Sporting News, “Manny dove from dawn till midnight.” So focused on his task was he that he missed the January 4 memorial service attended by his Pirate teammates.

After the tragic death of Roberto Clemente before the 1973 season, the Pirates slated Sanguillen to take Clemente’s place in right field. By mid-June, it was apparent that Sanguillen couldn’t adapt to playing the outfield and he was moved back to the catcher’s position. Sanguillen had another strong year in 1975, when he posted a .328 batting average, third in the National League batting championship behind Bill Madlock and Ted Simmons. In 1977, Sanguillen was traded by the Pirates to the Oakland Athletics for the services of then-A’s manager Chuck Tanner and $100,000 as a settlement of Tanner’s contract with the A’s.

After one season with the A’s, Sanguillen was traded back to the Pirates for Miguel Diloné and Elías Sosa. He played in only 85 games in 1978, mostly as a first baseman as Ed Ott and Duffy Dyer platooned at the catcher’s position. His playing time diminished further in 1979, playing in only 56 games, although he contributed a two-out, game-winning single and RBI for the Pirates in Game 2 of the 1979 World Series against the Orioles. The 1980 season was Sanguillen’s last in the majors, although he returned in 1982 to play in the Mexican League.

Before the Pirates’ win over the Cincinnati Reds at PNC Park on August 24, 2019, Sanguillen was inducted into the Hispanic Heritage Baseball Museum Hall of Fame in a special ceremony before over 26,000 fans.