He played college football for the Mississippi State Bulldogs, twice earning first-team All-SEC honors, and was selected by the Cowboys in the fourth round of the 2016 NFL draft.

Intended to serve as a backup in his rookie season, Prescott became the Cowboys' starting quarterback after starter Tony Romo was injured in the preseason.

[51] When Prescott joined the Cowboys for their rookie mini camp, he was issued #10 since veteran wide receiver Devin Street wore his college number 15.

[54] After Moore's injury, Prescott competed with second-year quarterback Jameill Showers for the backup job to established starter Tony Romo.

[55] However, the Cowboys coaching staff made the decision to start Prescott in the team's preseason opener at the Los Angeles Rams.

Working with the Cowboys' first-team offense, Prescott completed 10 of 12 passes for 139 yards and two touchdowns in one half of action, though Dallas would lose the game 28–24.

[62] Prescott threw his first NFL touchdown, a 17-yarder to wide receiver Dez Bryant, during the Cowboys' Week 3 matchup against the Chicago Bears.

[73] In Week 14, the Cowboys were dealt their second loss on the season, by a score of 10–7, from division rival New York Giants, with Prescott passing for 169 yards and one touchdown in the contest.

[76] In the Week 17 regular season finale, with the top playoff seed in the National Football Conference (NFC) clinched, the Cowboys decided to rest several starters.

[82] Prescott started his second professional season with 268 passing yards and a touchdown in the 19–3 victory over the New York Giants on Sunday Night Football.

[88] Prescott and the Cowboys followed up the big win over San Francisco with two victories over the Washington Redskins (33–19) and Kansas City Chiefs (28–17) to put the team at a 5–3 record.

[89][90] Going into the next game against the Atlanta Falcons, the Cowboys learned that they would be without running back Ezekiel Elliott for a six-game suspension, putting more pressure on Prescott for the success of the offense.

[94] Despite the setbacks, the Cowboys remained alive in playoff contention and responded with a 38–14 win over the Washington Redskins, where Prescott threw for two touchdowns.

[98] In a pivotal Week 16 matchup with the Seattle Seahawks on Christmas Eve, he recorded 181 passing yards but had two interceptions in the costly 21–12 loss, which eliminated the Cowboys from postseason contention.

[104][105] In Week 5, against the Houston Texans on NBC Sunday Night Football, he passed for 208 yards, one touchdown, and two interceptions in the 19–16 overtime road loss.

Prescott's performance in the game gave him a perfect passer rating, the first Dallas quarterback to achieve the feat since Craig Morton on October 5, 1969.

[139] In Week 10 against the Minnesota Vikings on NBC Sunday Night Football, Prescott threw for 397 yards, three touchdowns, and one interception in the 28–24 loss.

The deal included a $66 million signing bonus, the highest in NFL history at the time (it was surpassed in 2023 by quarterback Lamar Jackson's contract with the Baltimore Ravens).

[174] In Week 16, Prescott threw four touchdowns in a 56–14 blowout win against the Washington Football Team as the Cowboys would go on to clinch the NFC East division title.

On the last play with 14 seconds left, Prescott ran a quarterback draw up the middle for 17 yards, and was unable to spike the ball to stop the clock from running down.

[178] Despite the loss, Prescott was named NVP (Nickelodeon Valuable Player) with more than 81 percent of the online vote, becoming the second losing quarterback to do so in as many years.

[181] In Week 1 against the Tampa Bay Buccaneers, Prescott struggled, completing 14 of 29 passes for 134 yards and an interception before leaving the game in the fourth quarter with a right thumb injury in the 19–3 loss.

[190] In the season opener against the division rival New York Giants, Prescott completed 13 of 24 passes for 143 yards, shutting them out 40–0 in a blowout victory.

[197] After the bye week, Prescott threw 25-of-31 completions for 304 yards, four passing touchdowns, and an interception as the Cowboys defeated the Los Angeles Rams 43–20 in their 11th consecutive home victory.

[205][206] In Week 15 against the Buffalo Bills, Prescott struggled throughout the game, taking three sacks and completing 21 of 34 passes for 134 yards and an interception in a 31–10 loss.

[209] In the regular season finale against the Washington Commanders, Prescott completed 31 passes out of 36 attempts for 279 yards, four touchdowns, and an interception, leading the Cowboys to a 38–10 blowout victory and clinching the NFC East.

7 seeded Green Bay Packers in the Wild Card Round, Prescott threw two interceptions in the first half, with one of them returned for a touchdown as the Cowboys fell into a 27–0 hole that they could not recover from, as they lost 48–32.

[217] Four days later, in a Week 4 matchup with the New York Giants on Thursday Night Football, Prescott completed 22 of 27 passes for 221 yards and two touchdowns in a 20–15 win.

[221] On November 12, Cowboys owner Jerry Jones announced Prescott would undergo hamstring surgery and miss the rest of the season.

[258] On November 26, 2023, Prescott's girlfriend Sarah Jane Ramos announced via Instagram that the couple were expecting the birth of a baby girl.