On May 8, 2015, Deontay Wilder announced that he would make his first defense in his home state of Alabama, which would be the first heavyweight title fight held in the state. Wilder last fought in Alabama in 2012. Showtime confirmed they would televise the bout live on June 13th at Bartow Arena, Birmingham, Alabama. Shortly after, WBC #14 Eric Molina (23-2, 17 KOs) was announced as Wilder's opponent. After receiving some backlash for choosing Molina as his first defense, Wilder claimed there were other options, but their asking prices were too high. Molina was aiming to become the first Mexican-American world heavyweight champion in history. A sold-out crowd of 9,347 was announced. Wilder dominated, knocking down Molina near the end of round four, twice in the fifth, and knocking him out onto his back in the ninth round. Wilder showed respect for Molina after the bout, stating "I was really surprised he kept coming and hanging in there. A lot of people said he wouldn't even be around, he wouldn't last. There were a lot doubters, but he showed a lot of heart, and I needed that kind of guy to fight here in Alabama." Wilder was ahead on all three judges' scorecards at the time of stoppage 90-77,89-78, and 89-78. According to CompuBox Punch stats, Wilder landed 141 of 303 thrown (47th) whilst Molina landed just 49 of 188 (26%). The fight aired on Showtime and averaged 678,000 viewers. Wilder earned $1.4 million for the fight compared to Molina, who received a $250,000 purse.

Wilder vs. Duhaupas

In August 2015, it was announced that Wilder would make his second defense against WBC #12 Johann Duhaupas (32-2, 20 KOs) on September 26 at the Legacy Arena, Alabama. In front of a hometown crowd of 8,471 in attendance, Wilder beat Duhaupas by TKO in the eleventh round. Duhaupas, who was battered and bloodied, claimed he still had plenty of fight left when referee Jack Reiss waved off his brave challenge. Duhaupas had never been stopped before in his career inside the distance. It was a very one sided fight, after taking punishment in round seven, referee Jack Reiss went over to Duhaupas' corner telling him he would need to do more or he would stop the fight. Wilder was ahead 100-90, 99-90, and 99-91 on judges' scorecards at the time of the stoppage, having landed 326 of 587 punches thrown (56%) whilst Duhaupas landed 98 of 332 (30%). In the post fight, Wilder praised Duhaupas' toughness, saying "We knew he was tough. We knew he was mentally tough. We knew he was going to come. That's why you can't criticize nobody you don't know. The most scariest people are the ones you don't know." For the fight, Wilder made $1.4 million and Duhaupas earned a $140,000 purse. The fight was the main event of Premier Boxing Champions on NBC and averaged 2.2 million viewers, peaking at 3 million viewers.

In December 2015, Showtime confirmed that terms had been agreed for Wilder to defend his WBC title against Polish Boxer Artur Szpilker (20-1, 15 KOs) on January 16, 2016, at the Barclays Center, Brooklyn, New York, where the winner would be scheduled to fight WBC mandatory challenger Alexander Povetkin. A crowd of 12,668 mostly pro-Polish fans was announced. Szpilka looked very strong as the bout began, and won the first three rounds with his awkward southpaw stance, rapid foot movement, and talent for slipping punches. Szpilka made Wilder appear wild with his punches, as Wilder missed 175 punches thrown at Szpilka, mostly head punches. Entering round nine, Szpilka, aware from the ring commentators he could no longer win the fight on the cards, changed strategy and took a gamble. Going to the inside, Szpilka swung for the rafters, but Wilder read Szpilka and connected first with a powerful right hand to the face. Szpilka fell to the canvas, and his head jerked backwards in a reflex motion, abruptly ending the competitive contest and sending the ringside physicians and emergency medical personnel immediately into the ring. At the time of he stoppage, Wilder was winning the bout with the scores of 78-74 (twice) and 77-75. Wilder reportedly earned a career-high $1.5 million compared to Szpilka who had a $250,000 purse. The fight averaged 500,000 viewers and peaked at 623,000 viewers.

After the fight, newly crowned heavyweight champion Tyson Fury entered the ring going face-to-face in a heated verbal exchange with Wilder, calling him out. In the post fight press conference, Wilder rated his performance at 5/10. Wilder was not in a celebratory mood and said his concerns for Szpilka meant he was not in the mood for the confrontation with Fury. Wilder explained "We risk our lives in there for your entertainment. I want to knock my opponents out, but not hurt them. I want them to be able to go home to their family." Szpilka regained consciousness before leaving the ring on a stretcher, and recovered. The knockout was voted "Knockout of the Year" by Premier Boxing Champions.