Jones attended Glenville High School in Cleveland, Ohio, where he played football for Ted Ginn, Sr., leading the Tarblooders to the OHSAA D-I Championship game in 2009. While at Glenville, Jones also lettered in basketball and track. Jones was ranked by Rivals.com as a three-star recruit. He committed to Ohio State University in October 2011. In order to improve his academic standing, Jones attended Fork Union Military Academy for a semester prior to his enrollment at Ohio State University in January 2012.
Jones redshirted as a freshman and thus did not play, but nevertheless drew controversy when he posted the following on his Twitter account:
The tweet received heavy criticism and Jones was suspended for one game. The tweet was featured as an example of bad social media behavior in the "Best Practices on Social Media" section of a textbook for "The Ole Miss Experience," a freshman year class at the University of Mississippi. In March 2014, head coach Urban Meyer described Jones as a "different guy" who was "making progress in the classroom." Later, Jones provided context for the tweet:
Ultimately, on May 7, 2017, Jones graduated from Ohio State with a bachelor's degree in African-American Studies.
Cardale was sparingly used during his freshman season after red-shirting the 2012 season, playing only 39 snaps, attempting one pass and rushing for 128 yards and a touchdown on 17 carries.
After entering the 2014 season as a redshirt sophomore, third on the Buckeyes' depth chart, Jones made his first start of his college career in the Big Ten Championship Game in place of J. T. Barrett, who had been injured the prior week versus Michigan. Jones led the #6 (AP) ranked Buckeyes squad to a 59–0 victory over the #11 ranked Wisconsin Badgers, on the eve of the NCAA football committee's inaugural playoff selection. Jones was named MVP of the game.
Cardale Jones made the second start of his college career, and the Ohio State Buckeyes defeated #1 ranked Alabama Crimson Tide 42–35 in the Allstate Sugar Bowl to advance to the College Football Playoff National Championship against the Oregon Ducks. In the championship game he excelled once again and led the Buckeyes to a 42–20 victory over the Ducks. Jones recorded 280 all-purpose yards, scoring two touchdowns. He completed 16 of 23 attempted passes for 242 yards, with one touchdown and one interception and ran for another 38 yards and a touchdown. The day after winning the National Championship, Jones discussed his future football career. In a news conference, Jones said that while he did not officially rule out declaring for the 2015 NFL Draft, he believes that he is "not ready for that level yet," partly because he has only started in 3 college football games. Jones confirmed on January 15, 2015 that he would not declare for the 2015 NFL Draft, and would stay with Ohio State for at least another year, most probably until he graduated.
After a competition with Barrett that lasted the entire offseason, Jones was named the Buckeyes' starting quarterback immediately before gametime in Ohio State's season opener at Virginia Tech. Both he and Barrett remained listed as co-starters on the depth chart headed into September 12 meeting with Hawaii. He set career highs in passing yards and completions and passing yards against Maryland on September 10, 2015 with 21 completions, 291 passing yards, and two passing touchdowns. After Ohio State's final home game he announced his intention to enter the 2016 NFL Draft.
At the 2016 NFL scouting combine, Cardale suffered a hamstring injury during his second 40-yard dash attempt, ending his workout prematurely.
Despite only starting 11 games in his college career, Jones was drafted in the fourth round of the 2016 NFL draft, with the 139th overall selection, by the Buffalo Bills. On June 7, 2016, the Bills signed Jones to a rookie contract. In 2016, he was inactive for the first 15 games of the season as the third-string quarterback behind primary backup EJ Manuel and starter Tyrod Taylor. With Taylor being inactive for the final game of the season, Jones was promoted to second string. Jones entered the game to begin the fourth quarter after Manuel was benched. Jones completed 6-of-11 passes for 96 yards and no touchdowns with one interception.
On July 26, 2017, Jones was traded to the Los Angeles Chargers in exchange for a conditional draft pick.