Darren was selected by the Baltimore Ravens in the sixth round of the 2015 NFL Draft with the 204th overall selection, which was acquired in a trade in exchange for Rolando McClain. On October 29, 2015, Waller was placed on the injured reserve list, ending his season. On July 1, 2016, Waller was suspended for the first four games of the 2016 NFL season for violating the substance-abuse policy. On June 30, 2017, Waller was suspended for one year without pay for again violating the league's substance-abuse policy. On August 7, 2018, Waller was reinstated by the league after the year-long suspension. He was waived on September 1, 2018 and was signed to the practice squad the next day.
On November 26, 2018, Waller was signed by the Oakland Raiders off the Ravens' practice squad. During the 2018 season, he had six receptions for 75 yards. On Hard Knocks with the Raiders, he was featured in an episode detailing his struggle with substance abuse and steps taken to overcome it. In Week 1 of the 2019 season against the Denver Broncos, Waller caught seven passes for 70 yards in the 24–16 win. During Week 3 against the Minnesota Vikings, Waller finished with 134 receiving yards on 13 receptions, marking his first career game with over 100 yards, but the Raiders lost 14–34. On October 16, 2019, Waller signed a three-year contract extension with the Raiders through the 2023 season. In Week 7 against the Green Bay Packers, Waller caught seven passes for 126 yards and two touchdowns in the 42–24 loss. In Week 13 against the Kansas City Chiefs, Waller caught seven passes for 100 yards in the 40–9 loss. In Week 14 against the Tennessee Titans, he caught seven passes for 63 yards in a 42–21 loss. During Week 15 against the Jacksonville Jaguars, Waller finished with eight catches for 122 receiving yards as the Raiders lost 16–20. In Week 17 against the Denver Broncos, Waller caught six passes for 107 yards, including a 75 yard catch, during the 15–16 loss. Waller was named as an alternate to the 2020 Pro Bowl, and after the Kansas City Chiefs advanced to the Super Bowl, he was originally supposed to be named in as a replacement for Travis Kelce, but he had recently had thumb surgery and was unable to play. Jack Doyle was instead named as Kelce’s alternate. Waller finished the 2019 season with 90 receptions for 1,145 receiving yards and three receiving touchdowns.