Walker first saw action in his redshirt freshman season when Collin Ellis went down with a series of injuries. In his first career game, Walker returned an interception for a touchdown against Penn State that capped a Northwestern win. In his first full season as a starter, Walker found success as he recorded 122 tackles to lead the team and 20.5 tackles for loss which was fourth in the nation. For his performance that season, Walker received All-American recognition from the AP and Sports Illustrated as well as Consensus First-Team All Big 10 honors. On November 29, 2016, Walker was named Second Team All-Big Ten.
The Indianapolis Colts selected Walker in the fifth round of the 2017 NFL Draft. Walker was the 20th linebacker drafted in 2017. On May 11, 2017, the Indianapolis Colts signed Walker to a four-year, $2.66 million contract that includes a signing bonus of $265,413. Walker missed organized team activities due to Northwestern's quarters schedule and the league's rules on rookies being unable to join their team until their school's final semester had concluded. Upon entering training camp, Walker competed to be a starting inside linebacker against Sean Spence, Antonio Morrison, Jon Bostic, and Edwin Jackson. Head coach Chuck Pagano named Walker a backup inside linebacker to begin the regular season, behind Jon Bostic and Antonio Morrison. He made his professional regular season debut in the Indianapolis Colts' season-opener at the Los Angeles Rams, but exited in the second quarter of their 46–9 loss after sustaining a hamstring injury. His hamstring injury sidelined him for the next three games. In Week 5, he aggravated his hamstring injury during the third quarter of a 26–23 win against the San Francisco 49ers and was inactive for the next three games. On December 29, 2017, Walker earned his first start after Jon Bostic was ruled inactive due to an injury. He collected a season-high nine combined tackles in the Colts' 23–16 loss at the Baltimore Ravens in Week 16. On December 31, 2017, the Indianapolis Colts fired head coach Chuck Pagano after the Colts finished 4–12 in 2017. He finished his rookie season in 2017 with 22 combined tackles in ten games and two starts.
2018
On February 11, 2018, the Indianapolis Colts hired former Philadelphia Eagles'offensive coordinatorFrank Reich as their new head coach. Defensive coordinatorMatt Eberflus opted to change the base 3-4 defense and implemented a base 4-3 defense. Walker entered training camp slated as the starting middle linebacker, but saw competition from Najee Goode. On July 31, 2018, it was reported that Walker had injured his groin in the first week of training camp and was sidelined for the remainder of training camp and all four preseason games. Head coach Frank Reich named Walker the starting middle linebacker to start the regular season in 2018, alongside outside linebackers Najee Goode and rookie Darius Leonard. On September 23, 2018, Walker recorded nine combined tackles and made his first career interception off a pass by Eagles' quarterback Carson Wentz during a 20–16 loss at the Philadelphia Eagles in Week 2.
2019
In week 3 against the Atlanta Falcons, Walker recorded a team high 14 tackles as the Colts won 27-24. In week 4 against the Oakland Raiders, Walker recorded a team high 10 tackles and forced a fumble on quarterback Derek Carr in the 31-24 loss. In week 13 against the Tennessee Titans, Walker recorded a team high 12 tackles and forced a fumble on running backDerrick Henry on the first play of the game which was recovered by teammate Malik Hooker in the 31–17 loss. In week 16 against the Carolina Panthers, Walker recorded 10 tackles, sacked rookie quarterback Will Grier once, and intercepted a pass thrown by Grier during the 38–6 win. In week 17 against the Jacksonville Jaguars, Walker recorded a team high 16 tackles during the 38–20 loss.
