Sandberg made his major league debut as a shortstop for the Philadelphia Phillies in 1981. Thought to have little future with the club except as a utility infielder, he was traded along with shortstop Larry Bowa to the Cubs for shortstop Ivan DeJesus prior to the 1982 season.

The Cubs, who initially wanted Sandberg to play center field, installed him as their third baseman, and he went on to be one of the top-rated rookies of 1982. However, Sandberg was displaced by Chicago's free-agent signing of veteran Ron Cey following the 1982 season, so Sandberg moved to second base, where he became a star. After winning a Gold Glove Award in his first season at the new position, Sandberg emerged with a breakout season in 1984, in which he batted .314 with 200 hits, 114 runs, 36 doubles, 19 homers and triples, and 84 RBI. He nearly became the first player to collect 20 doubles, triples, home runs, and stolen bases in the same season (a feat which has yet to be accomplished), led the Cubs to the National League's Eastern Division title, and won Most Valuable Player honors.

One game in particular was cited for putting Sandberg (as well as the 1984 Cubs in general) "on the map", a NBC national telecast of a Cubs-Cardinals game on June 23, 1984, in which Sandberg twice hit game tying home runs in late innings off former Cubs closer Bruce Sutter who was by then the Cardinals ace closer. As NBC play-by-play man Bob Costas said when Sandberg hit that second home run, "Do you believe it?!" The game is sometimes called The Sandberg Game, although the actual winning run for the Cubs was driven in by a single from the bat of Dave Owen.

Sandberg established himself as a perennial All-Star and Gold Glove candidate, making 10 consecutive All-Star appearances and winning 9 consecutive Gold Gloves from 1983 to 1991. His career .989 fielding percentage is a major league record at second base.

In 1990, he led the National League in home runs - a rarity for a second baseman - with 40. Sandberg, Brady Anderson and Barry Bonds are the only players to have both a 40-homer (1990) and 50-steal (1985) season during their careers. Sandberg played a major league-record 123 straight games at second base without an error.

After struggling early in the season, Sandberg retired in 1994. While he had been a historically slow starter throughout his entire career, his 1994 start was slower than normal. In his book, Second To Home, Ryne said, "The reason I retired is simple: I lost the desire that got me ready to play on an everyday basis for so many years. Without it, I didn't think I could perform at the same level I had in the past, and I didn't want to play at a level less than what was expected of me by my teammates, coaches, ownership, and most of all, myself." He also said in the book that at the time of his retirement, to the best of his knowledge, eveything was fine with his marriage and that he wanted to be at home with his kids. He came back for the 1996 and 1997 seasons, retiring permanently at the age of 37 with a career batting average of .285, and a record 277 home runs as a second baseman; this record was surpassed in 2004 by Jeff Kent.

His nephew Jared Sandberg was a third baseman for the Tampa Bay Devil Rays.

Since retiring, Sandberg has kept a low profile. In 2003, Sandberg accepted his first marketing deal since his retirement, agreeing to be spokesman for a Chicago bank. He also appeared on ESPN Radio 1000 as an analyst during the 2004 baseball season. He currently serves as a spring training instructor for the Cubs in Mesa, Arizona. He also writes columns on baseball for Yahoo! Sports.

Not especially known for public speaking, Sandberg delivered what many traditionalist fans considered a stirring speech at his Hall of Fame induction ceremony 2005. He thanked the writers who voted for him. because it meant that he played the game the way he had been taught it should be played. He spoke several times of respect for the game, and chided a subset of current players who, in his opinion, lacked that respect.

He followed up on his Hall of Fame induction by becoming only the fourth Chicago Cub to have his number retired. On August 28, 2005, Ryne Sandberg had his number 23 retired in a ceremony at Wrigley Field, before a Cubs game against the Florida Marlins. He joined Ernie Banks, Billy Williams, and Ron Santo in the elite group. His number had already been de facto retired, as no other Cub had been assigned the number since Sandberg's active playing days had ended.

Coincidentally, Chicago Bulls great Michael Jordan, whose career in Chicago overlapped Sandberg's significantly, also wore number 23, giving Chicago two superstars with the same retired number.

In his capacity as a Cubs spring training instructor, Sandberg still wears uniform number 23.