He will be the third starting quarterback for the Broncos this season after Joe Flacco (now on injured reserve) and Brandon Allen, and Denver's seventh different starter since Week 9 of the 2017 season, when Brock Osweiler started in place of an injured Trevor Siemian.
Lock, the 42nd overall pick in April's draft, had been on injured reserve since the start of the regular season. He suffered a right thumb injury in an Aug. 19 preseason loss to the San Francisco 49ers and did not participate in a full practice again until Nov. 12.
The Broncos officially activated Lock off IR on Saturday and waived rookie quarterback Brett Rypien. Rypien had been on the roster all the way through the offseason program, training camp and through the regular season to this point.
The switch at quarterback comes as the Broncos' offense has struggled much of the season. They are coming off a 134-yard performance in a 20-3 loss to the Buffalo Bills last Sunday -- the team's lowest single-game output since 1992 and eighth-lowest in franchise history.
The Broncos, at 3-8, have scored more than 16 points just four times this season, and they are ranked 28th in the league in scoring and 27th in total offense.
Lock took most of the snaps with the starting offense in practice this week and was the first quarterback in line in drills during the open periods of practice as well. The Broncos held a walk-through practice on Saturday.
ESPN's Jeff Legwold contributed to this report.