After graduating from Jesuit High School of Tampa, Piniella began his professional playing career when the Cleveland Indians signed him as an amateur free agent in 1962. Piniella, at the age of 20, played in his first major league game in 1964 with the Baltimore Orioles. At 24, his second major league season was with the Indians. Piniella played for the Kansas City Royals from 1969-1973, winning AL Rookie of the Year in 1969. That was followed by 11 years as a member of the New York Yankees.

He wore uniform number 24 for the Orioles, and 23 for the Indians. His longer stretches were wearing number 9 for the Royals, and 14 on the Yankees.

He was the first player to come to bat in Kansas City Royals history. On April 8, 1969, he led off the bottom of the 1st against left-hander Tom Hall of the Minnesota Twins. He doubled to left field, then scored on an RBI single by Jerry Adair.

Piniella coached the Yankees in the late 1980s. He then managed the Cincinnati Reds in the early 1990s, winning the World Series in 1990. From 1993-2002, he managed the Seattle Mariners, winning the AL Manager of the Year award in 1995 and 2001.

Often known for his aggressive and sometimes explosive behavior, Piniella is one of the most-ejected managers in major league history. He has a reputation for being less than patient with pitchers, often sending his pitching coach to remove them from the game.

In his first two seasons with the Devil Rays, Piniella was able to improve the team somewhat, and they won a franchise-record 70 games in 2004, which was also their first season in which they did not finish last in their division. During the 2005 season, Piniella was very critical of Devil Rays' management for focusing too much on the future and not enough on immediate results, and for not increasing payroll quickly enough to field a competitive team (they started the season with a $30 million payroll, which was the lowest in the major leagues).

Tensions eventually made Piniella step down as Devil Rays' manager on September 21, 2005. He had one season remaining on his contract that he signed in October 2002, but agreed to a $2.2 million buyout of his contract, instead of his original $4.4 million that he was due, had he decided to manage the Devil Rays for one more season. He will also receive $1.25 million in deferred salary from 2003.

After parting ways with the Devil Rays, Piniella has recently become a color commentator for Fox Sports, having joined Joe Buck and Tim McCarver in calling postseason baseball games. There had been speculation that if Joe Torre didn't return to the Yankees for the 2006 season, Piniella would be considered for the managerial position. That speculation ended on October 18, 2005, when it was announced that Torre was going to remain with the Yankees organization. Piniella is considering staying with Fox Sports on a permanent basis, to continue calling games with Buck and McCarver next season.