Abstract Theoretical models and experimental evidence suggest that cortico-striatal-cerebellar networks play a crucial role in mediating motor sequence learning. However, how these different regions interact in order to mediate learning is less clear. In the present fMRI study, we used dynamic causal modeling to investigate effective connectivity within the cortico-striatal-cerebellar network while subjects performed a serial reaction time task. Using Bayesian model selection and family wise inference, we show that the cortico-cerebellar loop had higher model evidence than the cortico-striatal loop during motor learning. We observed significant negative modulatory effects on the connections from M1 to cerebellum bilaterally during learning. The results suggest that M1 causes the observed decrease in activity in the cerebellum as learning progresses. The current study stresses the significant role that the cerebellum plays in motor learning as previously suggested by fMRI studies in healthy subjects as well as behavioral studies in patients with cerebellar dysfunction. These results provide important insight into the neural mechanisms underlying motor learning.