Gaethje began wrestling at the age of four. He attended Safford High School, where he was a four-time finalist and two-time state champion (AIA). He still holds the seventh-most near falls (218) and the ninth-most team points scored (1057.5) in the history of the state as a wrestler. Gaethje also played football and baseball in high school.
Gaethje graduated from Safford High School with a 191–9 record. He initially applied to a small college in Arizona as he wanted to stay close to his family, but instead accepted an offer from the NCAA Division I program at the University of Northern Colorado. As a freshman, Gaethje had an 18–9 record, including a third-place finish at the Oregon Wrestling Classic. In his sophomore season, he qualified for the 2009 NCAA Division I 157 lb Championship, where he posted a 0–2 record. He finished the season with a 14–4 record and was named to the Western Wrestling All-Conference First Team.

As a junior, Gaethje went 5–2 at the 2010 NCAA Division I 157 lb Championship to earn 7th place and All-American status. This made him the first Northern Colorado wrestler to attain Division I All-American status since Larry Wagner in 1970. Gaethje dropped down to the 149 lb division for his senior year, but had struggles with weight cutting. He won true-second at the NCAA Western Regional Championships and so qualified for the 2011 NCAA Division I 149 lb Championship, where he posted a 1–2 record to end his senior season with a 17–8 record.

In June 2020, it was announced that Gaethje would be inducted into the University of Northern Colorado Athletics Hall of Fame for his achievements in wrestling.

Gaethje first came into contact with mixed martial arts (MMA) as a freshman at the University of Northern Colorado, when he wrestled Ultimate Fighting Championship (UFC) fighters such as Georges St-Pierre, Clay Guida and future opponent Donald Cerrone. Afterward, he talked to his coaches about his intentions on trying out the new sport, to which he was told that he had to get his grades up in order to get an amateur bout. After improving his grades, Gaethje made his amateur debut during the pre-season of his sophomore year (08'-09') on August 2, 2008, where he scored a slam knockout on his opponent.

After amassing a 7–0 amateur record, Gaethje made his professional debut on August 20, 2011, against future UFC fighter Kevin Croom. Gaethje won the fight in the first round via KO due to a slam after Croom attempted a submission. On the regional circuit in Colorado and Arizona, Gaethje compiled an undefeated 7–0 professional record, with 6 stoppage wins. One of his early victories was over UFC veteran Drew Fickett. Gaethje won by knockout 12 seconds into the first round.
Gaethje was signed by the World Series of Fighting on December 2, 2012, and made his debut on March 23, 2013, at WSOF 2 against Gesias Cavalcante, finishing the fight in the first round through TKO (doctor stoppage) after opening a cut above Cavalcante's left eye.

On June 14, 2013, he fought Brian Cobb at WSOF 3, eventually winning via TKO from leg kicks in the third round.

Afterward, Gaethje fought Dan Lauzon at WSOF 6 on October 26, 2013, finishing Lauzon by knockout with a right uppercut in the second round.

The three stoppage victories secured Gaethje a shot at the inaugural WSOF Lightweight Championship, in the headline bout of WSOF 8 against Richard Patishnock on January 18, 2014. Gaethje dispatched Patishnock in the first round via TKO to become the first WSOF Lightweight Champion.

His first title defense was at WSOF 11 against Nick Newell on July 5, 2014. Gaethje won the fight with a right hook TKO in the second round.

On November 15, 2014, Gaethje faced UFC veteran and former training partner Melvin Guillard at WSOF 15. The fight was ruled a non-title contest after Guillard missed weight. He scaled at 158.8 lbs, nearly 4 lbs over the 155 lb limit, and 50% of his purse went to Gaethje. Gaethje won the bout via split decision.

He then went on to fight Luis Palomino at WSOF 19 on March 28, 2015. Gaethje defended his title by stopping Palomino via TKO in the third round after a combination of leg kicks and punches. The Los Angeles Times named this fight as the best fight of 2015.

Gaethje had a rematch against Palomino on September 18, 2015, at WSOF 23 and defended his belt again, finishing Palomino in the second round by TKO.

At WSOF 29 on March 12, 2016, he defended his belt against Brian Foster via TKO due to leg kicks at 1:43 of the first round. Three days later, Gaethje was …

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As a two-time Arizona State high school champion and an NCAA Division I All-American, Gaethje has some of the best wrestling credentials in the UFC's lightweight division. Despite his elite wrestling pedigree, he rarely looks for takedowns, instead preferring an entertaining stand-up fighting style. He is well known for the knockout power in his punches, and his debilitating leg kicks. When asked after his loss to Poirier in 2018 why he did not use his wrestling in the bout, Gaethje said, "I’ve been wrestling my whole life. I should’ve and could’ve took him down a couple of times, especially when I had him rocked just to steal a round or two. For some reason, my mind will not let me do it. I think I sold myself so hard on the fact that this is not wrestling. It gets you tired. If I’m going to get tired, I’d rather it be from fighting and not from wrestling. That’s the reason why I never wanted to wrestle. But I did so much cardio this camp that it would not have been a problem for me to turn it into a wrestling match, but I just can’t do it, it would not be fun for me."

In a 2020 ESPN interview, Gaethje stated he realized after transitioning from wrestling to mixed martial arts that, while winning was still important, entertaining the fans could earn him more money. He said, "There can be guys out there who are 13–0 with 13 decisions, and they're not [even] getting paid $5,000 to fight because nobody is watching. I've gotten opportunities on the biggest stages because of the way I fight. I've never not wanted to win a belt, but I wanted to make money, and the surest way to make money in this sport was to be exciting." According to Gaethje's coach Trevor Wittman, the back-to-back losses against Alvarez and Poirier caused Gaethje to change his mentality. Although he is still a pressure fighter, Wittman said that Gaethje now takes fewer risks and is more selective about when to trade punches. Wittman stated, "I asked him after those two losses, 'Is your purpose still to be the most exciting fighter in the world?' And he said, 'Not really, Coach. I want to be a UFC champion.'"