Siakam was elevated to a starting role after playing well as an energizer off the bench in the past 10 games. He started 28 games last year, but came off the bench after missing the season opener to attend his father's funeral in Cameroon.
Siakam scored the Commodores' first six points and finished 7 of 8 from the floor and 3 of 4 from the foul line.
Wade Baldwin IV scored 16 for Vanderbilt (8-3), including two 3-pointers. Damian Jones entered the game as the SEC's fifth-leading scorer and added 15 points and six rebounds.
Siakam also led the Commodores with eight rebounds and Vanderbilt outrebounded Penn 39-24, including a 29-14 edge on the defensive glass.
After being outrebounded in Saturday's loss at Georgia Tech, Vanderbilt posted a 22-9 rebounding edge in the first half on their way to a 40-29 lead at the break.
Tony Hicks led Penn (3-6) with 16 points and Matt Howard added 11.
Jones scored 13 points during a key stretch in the first half as the Commodores made a 20-7 run to take a 30-22 lead. Vanderbilt pulled away to a 57-32 lead after opening the second half with a 17-3 run.
Vanderbilt coach Kevin Stallings won his 300th game with the Commodores. He is in his 16th season at the private school in Nashville and is the winningest coach in school history.
The Commodores outscored the Quakers 40-20 in the paint and took advantage of its depth by outscoring Penn's bench 29-9.
It was the first meeting between the schools since Vanderbilt's one-point win in 1986.
Vandy blasts Penn, 79-50
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