McAfee missed two relatively short field goals in WVU’s 13–9 loss to a Pitt Panthers team with only four wins; ultimately taking the Mountaineers out of the BCS National Championship Game. He was named to the 2007 Lou Groza Award semi-finalist list for the best collegiate kicker. McAfee earned Big East Special Team Player of the week honors three times in 2007 and was named second-team All-Big East. He earned West Virginia’s Scott Shirley Award for the second consecutive year.

McAfee was drafted in the seventh round (222nd overall) of the 2009 NFL Draft by the Indianapolis Colts. McAfee was signed before training camp. He handled punting and kick-off duties for the Colts in 2009, as well as holding for extra-points and field goals, a position he had never played before. In 2009 McAfee helped Indianapolis win the AFC South, the AFC Championship, and helped the Colts reach Super Bowl XLIV.

A month before the NFL Draft, on March 22, 2009, McAfee was involved in a match against The WarPig at an IWA East Coast show in South Charleston, West Virginia. WarPig controlled much of the match, but McAfee hit him with a low blow and a super kick, securing an upset victory. Nine years later in March 2018, McAfee was present at an NXT show in Indianapolis, where he prevented Adam Cole from winning by disqualification in his match against Aleister Black. Instead, McAfee’s distraction was enough time for Black to recover and hit Cole with his finisher, Black Mass.

On October 20, 2010, McAfee was arrested and charged with public intoxication, a Class B misdemeanor. McAfee had been found shirtless and wet, and alleged to have swum in a canal in Broad Ripple, a popular nightclub area, at approximately 5:15 that morning after being reported by a woman who found him near her car. Police reported that he tested with a blood alcohol content of 0.15. The Colts later issued a one-game suspension to McAfee for his actions. Two weeks after being arrested, McAfee issued an apology for his actions. “Obviously I made a dumb decision on a night when things got out of control,” he said. “I will never put my team or my family through this kind of embarrassment again.”

In November 2011, McAfee chopped off his signature locks for Locks of Love, an organization that provides hairpieces for children who are suffering from long-term illness and are poor.

On January 4, 2014, McAfee tweeted a photo with Colts teammate Andrew Luck in the background, almost completely nude. McAfee, who was taking a picture of kicker Adam Vinatieri being interviewed in the locker room, apologized for the incident and was fined $10,000 by the Colts organization, according to his interview with The Bob & Tom Show. On March 7, McAfee announced he had signed a five-year contract to remain with the Colts.

McAfee was named the AFC Special Teams Player of the Month for September 2014. He led the NFL in punting average (45.6 yards) and touchbacks on kickoff (24), and converted the NFL’s only two successful onside kicks in the first four weeks of the season. In week 6, McAfee converted his third onside kick of the season, recovering the ball himself after it traveled the necessary 10 yards. On December 23, 2014, McAfee was selected to play in his first Pro Bowl, and on January 2, 2015, he was selected by the Associated Press as the First Team All-Pro punter.

On December 20, 2016, McAfee was named to his second Pro Bowl.

In May 2016, McAfee created a company named Shirts for America, to serve as a sponsor for Indycar driver Conor Daly for the 2016 Indianapolis 500 and to support both the Pat McAfee Foundation and Wish for Our Heroes.

On February 5, 2016, McAfee became a Guinness World Record holder by successfully kicking a 40-yard field goal while blindfolded. The record was surpassed two years later when Davis Brief, a fan of McAfee’s, kicked a 45-yard field goal while blindfolded on September 23, 2018.

On February 2, 2017, after eight seasons, McAfee retired from the NFL and stated he intended to join Barstool Sports as a contributor. He cited his recent knee operation (his third in four seasons) as a factor in his decision, as well as his fractured relationship with Colts’ general manager Ryan Grigson.

Following his retirement from football at the close of the 2016 season, McAfee joined Barstool Sports, where he developed the “Heartland” division of the company in Indianapolis and hosted The Pat McAfee Show on SiriusXM channel Barstool Power 85. McAfee announced his separation from Barstool Sports on August 31, 2018, citing a lack of transparency with the business operations of the company as his reason for leaving.

On November 24, 2018, McAfee made his college football broadcasting debut on Fox, calling a college football game between Baylor and Texas Tech. On December 30, McAfee made his NFL broadcasting debut on Fox, joining Justin Kutcher, Robert Smith, and sideline reporter Sarah Kustok for the Lions–Packers game.

McAfee is a regular on the nationally syndicated morning radio program The Bob & Tom Show, itself based in Indianapolis. He has described co-host Bob Kevoian as one of his best friends during an interview on the Off the Air Podcast hosted by sports commentator Chick McGee. In 2018, McAfee made his professional baseball debut for the Washington Wild Things as a right-fielder and guest first base coach. He made a putout in the outfield and went 0–3 at the plate, reaching second base on a throwing error before being replaced with a pinch runner.

During 2018, McAfee began appearing on WWE programming as a pre-show analyst for the company’s NXT TakeOver events, beginning with NXT TakeOver: New Orleans, where he continued his mini-feud with Adam Cole. He later appeared at NXT TakeOver: Chicago II, NXT TakeOver: Brooklyn 4 and NXT TakeOver: WarGames. In December, it was reported that he had formally signed a multi-year contract with WWE, and officially signed the contract in February 2019. He then began hosting live watch-along of WWE’s pay-per-views on YouTube, beginning with Fastlane, alongside a number of WWE wrestlers. In the buildup to WrestleMania, McAfee, his crew and various special guests travelled venue to venue in an RV, which was filmed for Pat McAfee’s Road to WrestleMania. Backstage at the event, McAfee got into an argument with Michael Cole, when Cole had criticized him for wearing tuxedo shorts. McAfee threatened to quit on the spot, and was sent to another room while the situation was dealt with. After Vince McMahon was shown an image of LeBron James at the 2018 NBA Finals, and that the outfit was similar to the one McAfee was wearing for WrestleMania, McMahon approved and McAfee was allowed to co-host the second hour of the pre-show, alongside Charly Caruso.

On July 29, 2019, Adam Schefter announced via Twitter that McAfee would be joining ESPN as the color analyst for their Thursday Night College Football broadcasts, alongside Matt Hasselbeck. Also, McAfee will be making regular weekly appearances on Get Up!. This news comes after McAfee had auditioned for on ESPN’s Monday Night Football after Jason Witten’s return to the Cowboys, though ESPN decided to retain its booth as-is. McAfee began making regular appearances on ESPN’s College GameDay in 2019.

On August 7, 2019, it was reported that McAfee would begin to host a two-hour, weekday radio show, The Pat McAfee Show, beginning September 9, 2019, syndicated by Westwood One and DAZN. The deal with DAZN also includes McAfee streaming his podcast on the service three times per week, and appearances in NFL-related shoulder content in regions where DAZN holds streaming rights to the league (primarily Canada and Germany).

McAfee became engaged to his girlfriend, Samantha Ludy, in February 2019. The two were married August 1, 2020, at Coxhall Gardens in Carmel, Indiana.

During the 2020 NFL season, despite being out of the NFL for four years, fans began making a push for McAfee to come out of retirement to play for his hometown Pittsburgh Steelers, who have struggled with their punting during the season. McAfee himself added to the rumors by immediately tweeting a video of him punting after the Steelers released Dustin Colquitt without immediately signing a replacement. The team ended up re-signing Jordan Berry, who had been the team’s punter for five years prior to the signing of Colquitt.

He was a sideline reporter for the XFL for some of its games in 2020. In 2020, McAfee and former linebacker A. J. Hawk began a podcast, McAfee & Hawk: Sports Talk.

On July 23, 2020, Cole was a guest on McAfee’s podcast. Cole became very frustrated with McAfee during the interview for saying that the Undisputed Era was the reason for his success and he would not have achieved all that he has on his own because he was a small guy. This would cause Cole to eventually curse out McAfee, break his microphone, push his friend (who suffers from colitis), and storm out of the interview. Triple H would appear on McAfee’s podcast a few days later to invite him to come to an episode of NXT to talk things out with Cole. McAfee appeared in the August 5 episode of NXT, appearing to have made up with Cole. However, later in the night, as McAfee was a guest commentator in a NXT tag team match between Bobby Fish and Kyle O’Reilly of the Undisputed Era and Fabian Aichner and Marcel Barthel of Imperium, Cole noticed McAfee at the commentary table and began to insult and attack McAfee, resulting in McAfee punting Cole’s head. The next day, Triple H challenged McAfee to a match on behalf of Cole on NXT TakeOver: XXX, which McAfee accepted. At the event, McAfee, in his first match for WWE, was defeated. McAfee has not ruled out becoming an in-ring competitor in the future. McAfee returned to NXT on October 21, 2020, interfering in a NXT tag team title match between Breezango (Fandango and Tyler Breeze) vs Danny Burch and Oney Lorcan, resulting Burch and Lorcan in winning the NXT Tag Team Championships and aligning with McAfee, in which all three turned heel. A week later, Pete Dunne aligned with McAfee after appearing to help Kyle O’Reilly go up against McAfee, Burch, and Lorcan.