Michigan's 2016 spring practice featured a quarterback battle between Speight, redshirt junior John O'Korn, redshirt junior Shane Morris, true freshman Brandon Peters and redshirt freshman Alex Malzone.
After spring practice, press reports indicated that Speight, O'Korn and Morris were leading the competition, in that order.
O'Korn and Speight were the starters in the April 1 spring game.
Speight passed for a touchdown and ran for another leading his team to a 14–13 win.

In August 2016, Speight and O'Korn entered training camp as Michigan's quarterback frontrunners.
Coach Harbaugh refused to reveal the identity of his starting quarterback prior to the opening game.
 On September 3, 2016, Speight was named the starting quarterback.
 In the opening game, Speight led Michigan to a 63–3 victory over Hawaii.
On Michigan's first play from scrimmage, Speight threw an interception on an attempted screen pass to Jake Butt.
 For the game, he completed 10 of 13 passes for 145 yards with three touchdown passes and one interception.

In his second start on September 10 against UCF, Speight completed 25 of 37 passes for 312 yards with four touchdown passes and no interceptions to earn Big Ten Offensive Player of the Week honors.

On October 1, Speight's tiebreaking fourth quarter touchdown pass to Amara Darboh against #8-ranked Wisconsin lifted Michigan to its first win against a top-10 opponent since the 2008 Wolverines beat the 2008 Badgers, ending a streak of 12 consecutive such losses.

After leading Michigan to a 9–0 start with a 59–3 victory in his career-high 362-yard passing performance against Maryland on November 5, Speight and Michigan lost to Iowa 14–13 on November 12.

Two days later, it was reported that Speight had endured a broken collarbone during the game and was feared lost for the rest of the season.

However, after missing one game against Indiana, Speight returned to the lineup to start against Ohio State in the rivalry game.
He posted 2 touchdowns, but had 2 interceptions and a critical fumble in the double-overtime loss.
Following the season, Speight was the third team All-Big Ten quarterback selection by both the coaches and the media (behind J. T. Barrett and Trace McSorley).

During the 2016 Capital One Orange Bowl, Speight and the Michigan offense struggled to generate offense against a dominant Florida State defensive line.
 Michigan managed just 6 points in the first half on two field goals (from kicker Kenny Allen).
 Michigan rallied late in the game, including Speight's only throwing touchdown of the night, eventually taking a 30–27 lead with 1:57 remaining in the game.
The lead was short-lived as Michigan gave up the game-winning touchdown with just 36 seconds remaining in the game.
 The ensuing Michigan possession ended with Florida State intercepting a Speight pass and running out the clock for a Florida State victory (33–32).
For the game, Speight completed 21 of 38 passes (55.3%) for 163 yards with one touchdown and one interception.
In 12 starts, Speight finished the year with 2,538 passing yards, 18 touchdowns, 7 interceptions, and completed 61.6 percent of his passes.
Michigan's 2016 spring practice featured a quarterback battle between Speight, redshirt junior John O'Korn, redshirt junior Shane Morris, true freshman Brandon Peters and redshirt freshman Alex Malzone. After spring practice, press reports indicated that Speight, O'Korn and Morris were leading the competition, in that order. O'Korn and Speight were the starters in the April 1 spring game. Speight passed for a touchdown and ran for another leading his team to a 14–13 win.
In August 2016, Speight and O'Korn entered training camp as Michigan's quarterback frontrunners. Coach Harbaugh refused to reveal the identity of his starting quarterback prior to the opening game.  On September 3, 2016, Speight was named the starting quarterback.  In the opening game, Speight led Michigan to a 63–3 victory over Hawaii. On Michigan's first play from scrimmage, Speight threw an interception on an attempted screen pass to Jake Butt.  For the game, he completed 10 of 13 passes for 145 yards with three touchdown passes and one interception. 
In his second start on September 10 against UCF, Speight completed 25 of 37 passes for 312 yards with four touchdown passes and no interceptions to earn Big Ten Offensive Player of the Week honors. 
On October 1, Speight's tiebreaking fourth quarter touchdown pass to Amara Darboh against #8-ranked Wisconsin lifted Michigan to its first win against a top-10 opponent since the 2008 Wolverines beat the 2008 Badgers, ending a streak of 12 consecutive such losses. 
After leading Michigan to a 9–0 start with a 59–3 victory in his career-high 362-yard passing performance against Maryland on November 5, Speight and Michigan lost to Iowa 14–13 on November 12. 
Two days later, it was reported that Speight had endured a broken collarbone during the game and was feared lost for the rest of the season. 
However, after missing one game against Indiana, Speight returned to the lineup to start against Ohio State in the rivalry game. He posted 2 touchdowns, but had 2 interceptions and a critical fumble in the double-overtime loss. Following the season, Speight was the third team All-Big Ten quarterback selection by both the coaches and the media (behind J. T. Barrett and Trace McSorley).
During the 2016 Capital One Orange Bowl, Speight and the Michigan offense struggled to generate offense against a dominant Florida State defensive line.  Michigan managed just 6 points in the first half on two field goals (from kicker Kenny Allen).  Michigan rallied late in the game, including Speight's only throwing touchdown of the night, eventually taking a 30–27 lead with 1:57 remaining in the game. The lead was short-lived as Michigan gave up the game-winning touchdown with just 36 seconds remaining in the game.  The ensuing Michigan possession ended with Florida State intercepting a Speight pass and running out the clock for a Florida State victory (33–32). For the game, Speight completed 21 of 38 passes (55.3%) for 163 yards with one touchdown and one interception. In 12 starts, Speight finished the year with 2,538 passing yards, 18 touchdowns, 7 interceptions, and completed 61.6 percent of his passes.
Wilton Speight