Thome grew up in Peoria, Illinois, as part of a large blue-collar family of athletes, who predominantly played baseball and basketball.

After stints with the Los Angeles Dodgers and Minnesota Twins, he made brief returns to Cleveland and Philadelphia, before ending his career with the Baltimore Orioles.

[7] One day during his youth, Thome sneaked into the Cubs' clubhouse at Wrigley Field in an unsuccessful attempt to obtain an autograph from his favorite player, Dave Kingman.

[5] As with his older brothers, Thome attended Limestone High School where he achieved all-state honors in basketball and as a baseball shortstop.

[16] The work paid off; in 1990, Thome hit .340 and totaled 16 home runs and 50 RBIs in 67 games playing at both the Rookie and Class A levels of the minor leagues.

[20] In 1993, playing mostly for the Charlotte Knights, the Indians' new Triple-A affiliate, he led the International League with a .332 batting average and 102 RBIs, complemented by 25 home runs in 115 games.

[20] An article in Sports Illustrated published in July 1998 commented that despite Thome's early career success (two All-Star Games and appearances in two of the previous three World Series), he was only "faintly famous" nationally and was not particularly well known outside of Cleveland or his hometown, Peoria.

His former teammate Jeromy Burnitz said, "You can't really say he's underrated, because everybody considers him one of the top hitters in the American League, but he's surrounded by so many good players, it's hard to stand out on that team.

[37][38] Thome hit 47 home runs in his first season with the Phillies, finishing one behind Mike Schmidt's single-season team record of 48 in 1980, and tied with Alex Rodriguez for the MLB lead in 2003.

[42] Thome missed a significant portion of the first half of the Phillies' 2005 season due to injury;[43] he compiled only a .207 batting average with seven home runs and 30 RBIs going into the All-Star break.

[45] The Phillies traded Thome and cash considerations to the Chicago White Sox on November 25, 2005, for outfielder Aaron Rowand and minor league pitching prospects Gio González and Daniel Haigwood.

[52] Thome became the 23rd major leaguer to reach the milestone and the third in the 2007 MLB season (the others were Frank Thomas and Alex Rodriguez), as well as the first ever to do it with a walk-off home run.

[52][53] Several family members including his father were on hand to witness the accomplishment,[54] which occurred at a game during which the White Sox distributed free Thome bobbleheads to fans.

[56][57] He hit a solo home run in the AL Central Tiebreaker game, which proved to be the difference as the White Sox defeated the Minnesota Twins, 1–0.

[62] On August 31, 2009, the White Sox traded Thome to the Los Angeles Dodgers along with financial considerations for minor league infielder Justin Fuller.

[84] On August 26, 2011, Thome waived his contractual no-trade clause to return to his first team, the Cleveland Indians, in exchange for future considerations for the Twins.

[37][85] On September 18, the clubs announced that Minnesota had received $20,000 for him, which Aaron Gleeman of NBC Sports called "silly" and "nothing"; Paul Hoynes of The Plain Dealer wrote that ticket and jersey sales alone from re-acquiring Thome covered the money they paid to acquire him.

[86][87] On September 23, Cleveland held a ceremony to honor Thome, and revealed plans to erect a statue depicting him in Heritage Park.

[99] On June 17, Thome became the fourth major league player to hit 100 home runs with three different teams, joining Reggie Jackson, Darrell Evans and Rodriguez.

[100] Six days later, Thome hit a pinch-hit walk-off home run in the ninth inning off of Jake McGee to beat the Tampa Bay Rays, 7–6.

After the game (which coincided with Howard's return from the disabled list), the team announced that Thome had been traded to Baltimore to serve as their designated hitter.

"[105]On July 20, Thome hit his first home run with the Orioles, his 610th of all time moving him past Sosa for seventh place all-time, against the Indians at Progressive Field.

"[111] In March 2014, Thome clarified that he was not officially retired; while he "loves" his front office job with the White Sox, he would "have to take" a call about him playing again.

[117] On February 23, 2022, Thome was announced as the new president of the Major League Baseball Players Alumni Association, succeeding Brooks Robinson.

[123][124] In 2011, Lindy's Sports described him as an "extremely patient veteran slugger who launches cripple fastballs and breaking-ball mistakes to all fields", though they did note that he struck out frequently, had poor speed, and should serve only as a designated hitter.

[18] He is an example of a "three-true-outcome" player; 47.6% of his career plate appearances resulted in either home runs, strikeouts, or walks, the highest of all time by nearly seven percentage points.

[5] In 1997, the Indians wore high socks for his birthday in August, but ended up wearing them for the remainder of the season out of superstition and eventually reached the World Series.

[5][141] In a piece for Philadelphia magazine discussing Thome's Baseball Hall of Fame prospects, sportswriter Stephen Silver wrote, "It's not just the numbers.

[145][146] Soon after the announcement of his front office position (which signified the end of his playing career), writers began to speculate as to whether Thome would make it to the Baseball Hall of Fame, and more specifically, whether he would gain entrance in his first year of eligibility in 2018.

[154] In 2013, after the November 17, 2013, tornado outbreak struck Washington, Illinois, just 15 miles (24 km) from his hometown, he and his wife pledged to donate $100,000 to relief efforts.