The duo have been long-term absentees from the first team with injuries, but both made it through 90 minutes as the Under-21s battled Wolves in freezing conditions
Both players featured in United's 4-0 victory over Norwich earlier this month, but dropped down to the reserves to continue the process of recovery from persistent injuries.
Smalling has been plagued by injuries this season, with thigh and metatarsal problems halting the strong progress he made in the last campaign, and limiting him to 19 appearances this season.
The 23-year-old was the victim of a two-footed lunge during the match which saw Zeli Ismail sent off, but after treatment the young defender was able to continue.
Anderson also completed the full 90 minutes as he steps up his recovery from persistent hamstring problems, spurning a couple of good opportunities to win the game for the home side at Moss Lane.
Both players emerged unscathed from the clash despite freezing conditions, and could now be set to return to first-team action in time to help United's pursuit of the Premier League and FA Cup.