McGinn totaled two goals and an assist while MacKinnon notched the first 3-point game of his career with a goal and two assists in the Avalanche's third straight win and eighth in 10 games.
Gabriel Landeskog added a pair of goals and Erik Johnson contributed three assists. Marc-Andre Cliche and Tyson Barrie also scored for the Avs.
Semyon Varlamov earned the victory with 27 saves.
Matt D'Agostini got the only goal for Sabres, who fell for the eighth time in 10 contests.
Ryan Miller started in net but was lifted after stopping 22-of-27 shots. Jhonas Enroth went the rest of the way, allowing two goals on 12 shots.