An outfielder, he played 18 seasons in Major League Baseball (MLB) with the Baltimore Orioles, Cleveland Indians, Kansas City Royals and New York Yankees.

Following his playing career, Piniella became a manager for the Yankees (1986–1988), Cincinnati Reds (1990–1992), Seattle Mariners (1993–2002), Tampa Bay Devil Rays (2003–2005), and Chicago Cubs (2007–2010).

He won the 1990 World Series championship with the Reds and led the Mariners to four postseason appearances in seven years (including a record 116-win regular season in 2001).

He was nicknamed "Sweet Lou", both for his swing as a major league hitter and, facetiously, to describe his demeanor as a player and manager.

[17] He made his major league debut that year on September 4 at the age of 21, appearing as a pinch hitter and grounding out in his first at bat.

[20] Piniella was selected by the Seattle Pilots in the 1968 expansion draft in October, but was traded after spring training on April 1, 1969 to the Kansas City Royals for John Gelnar and Steve Whitaker.

[17] He was the first batter in Royals history; on April 8 of their first season in 1969, he led off the bottom of the first inning against left-hander Tom Hall of the Minnesota Twins.

[30] The Cincinnati Reds let go of Tommy Helms after he managed the last 37 games of the 1989 season (marred by the permanent ban of player-manager Pete Rose).

[31] In his first year, the Reds won the World Series in a four-game sweep of the favored defending champion Oakland Athletics.

Two months later, Darling and the Major League Umpires Association sued for defamation to the tune of $5 million against Piniella.

While he stated that realized his own error in making the statement against Darling, the fact that he received no backing from the Reds played a key part in him not wanting to manage there.

After winning the 2001 AL Division Series against the Cleveland Indians, the Mariners dropped the first two games of the AL Championship Series to the New York Yankees, and Piniella held an angry post-game press conference in which he guaranteed the Mariners would win two out of three games in New York to return the ALCS to Seattle.

Following the 2002 season, Piniella requested out of his final year with the Mariners to manage the Tampa Bay Devil Rays.

[15][45] As compensation, the Devil Rays traded outfielder Randy Winn to the Mariners for infield prospect Antonio Pérez.

During the 2005 season, Piniella was critical of the Devil Rays' front office 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.

[54] However, on August 22, Piniella decided to resign after that day's game, stating that he wanted to care for his ailing 90-year-old mother.

After parting ways with the Devil Rays in 2005, Piniella was an analyst for Fox Sports, first joining Joe Buck and Tim McCarver calling the 2005 American League Championship Series.

[60] Piniella suffered what was described as a "mini-stroke" in June 2017, but sufficiently recovered to resume his role as senior advisor to baseball operations with the Cincinnati Reds for the 2018 season.

In late 2007, Piniella appeared in a television commercial for Aquafina bottled water in which he parodies his famous June 2, 2007 meltdown at Wrigley Field.

Piniella and Chicago White Sox manager Ozzie Guillén appeared in one commercial to advertise a local car dealership during the first half of the 2008 Crosstown series.