Motor behavior and sensorimotor activation of the cerebrum and cerebellum were measured before and after motor imagery-based mental practice (MP) and physical practice (PP) of a sequential motor task. Two-button-press sequences (A, B) were performed outside a magnetic resonance imaging scanner and at 2 Hz inside the scanner during a pretest. Participants (n = 39) completed PP, MP, or no practice (NP) of Sequence A for 1 week and were posttested. Sequence A performance improved 121%, 86%, and 4% for the PP, MP, and NP groups, respectively (p < 0.05), while Sequence B improved 56%, 40%, and 38% (p > 0.05). PP improvements were accompanied by increased striatal and decreased cerebellar activation, while MP improvements were accompanied by increased cerebellar, premotor, and striatal activation. The efficacy of MP for activating cerebral and cerebellar sensorimotor networks suggests that MP might be an effective substitute or complement to PP to activate compensatory networks for motor rehabilitation.