After playing college football for the Morehead State Eagles, Simms was selected in the first round by the Giants as the seventh overall pick in the 1979 NFL draft.

Simms was born in Springfield, Kentucky, on his grandfather's farm, a place now called Maple Hill Manor in Washington County, where he attended St. Dominic's Elementary.

[5] Walsh was so impressed that he planned to draft Simms in the third round, preferring him over the quarterback they ultimately took, Joe Montana of Notre Dame.

"[7] When Simms's name was announced by Commissioner Pete Rozelle in front of the audience at the draft in New York, his selection was booed loudly by the Giants fans in attendance.

[11] Simms won the first five starts of his rookie year in 1979;[12] he was 6–4 as a starter, threw for 1,743 yards and 13 touchdown passes, and was named to the NFL All-Rookie Team.

[15] In 1981, Simms threw for 2,031 yards, 11 touchdowns, and 9 interceptions on 54.4% completion percentage[15] before suffering a separated shoulder in a November 15 loss to the Washington Redskins.

Simms suffered a torn knee ligament in a preseason game against the New York Jets, preventing him from playing the entire 1982 season.

[17] Following the season, Ray Perkins resigned as head coach to take over the same position at the University of Alabama, and was replaced by the team's defensive coordinator Bill Parcells.

On his third drive, Simms suffered a season-ending injury when the thumb on his throwing hand hit a player's helmet on his follow-through.

"[19] However, in 1984, after many seasons plagued by injuries and up-and-down play, Simms finally emerged as a team offensive leader.

During his 1983 injury, offensive coordinator Ron Erhardt talked Simms into watching more game film, something he had not regularly done in college or the pros.

He gained a better understanding of NFL defenses, his team's formations, and pass protection schemes, and improved his ability to audible at the line of scrimmage.

In week 11, he completed a desperate fourth-and-17 pass to Bobby Johnson late in the game to set up Raul Allegre's game-winning field goal, which gave the Giants a 22–20 victory over the Minnesota Vikings.

In 1990, Simms was having one of his finest seasons, leading the NFC with the highest quarterback rating (92.7)[35] and the Giants to an 11–3 record, but his season was cut short due to a broken foot suffered in the Week 15 game against the Giants' eventual Super Bowl XXV opponent, the Buffalo Bills.

After the Giants' Super Bowl victory, Parcells resigned and was replaced by the team's running backs coach, Ray Handley.

Simms suffered a severe arm injury in a Week 4 loss to the Los Angeles Raiders and missed the remainder of the season.

[15] The Giants finished the 1992 season at 6–10, which led to Handley's firing and the hiring of former Denver Broncos coach Dan Reeves.

[37] Simms started all 16 games in 1993, being one of only seven quarterbacks to do so, and led the Giants to a resurgent 11–5 season including a victory over the Minnesota Vikings in the playoffs.

The surgery was successful, and team doctor Russell F. Warren's prognosis for recovery was excellent, and Simms was expected to be ready in time for training camp.

During an emotional speech, Simms stated that he wanted to don his jersey one final time, and throw "one more pass" to teammate Lawrence Taylor.

[48] Simms later commented, "[a]ll of a sudden it kind of hit me, I've put Lawrence in a really tough spot; national TV, he's got dress shoes and a sports jacket on, and he's had a few beers and he's going to run down the field and I'm going to throw him a pass.

Outside of football broadcasting, Simms co-hosted the Miss Universe 2002 pageant with actress and model Daisy Fuentes.

On November 13, 2014, Simms appeared uncredited on the episode "Just a Regular Irregular" of the CBS television series Elementary.

Furthermore, Simms was forced to settle a debt with Holmes by loaning him a Super Bowl ring for the purpose of advancing the investigation.