Neural mechanisms of skill acquisition across the lifespan are largely unknown. Neuroimaging in younger adults and research on neurodegenerative disorders suggests that perceptual-motor learning relies on the striatum, cerebellum, and prefrontal cortex. Our objective in this study was to explore whether individual differences in regional brain volumes modify the effects of age and sex on the acquisition of a perceptual-motor skill in healthy adults. The participants (N = 85, age 22-80) performed five 5-trial blocks of a mirror-drawing task on three separate days (for a total of 25 trials). Index of performance was time to completion and number of errors committed. All participants improved with practice, but younger adults performed better than their older counterparts, and women performed better than men. Four brain regions--lateral prefrontal cortex (LPFC), hippocampus (HC), cerebellar hemispheres (Cb) and the caudate nucleus (Cd)--were selected on the basis of the relevant literature and measured on MRI scans. All regional volumes were negatively associated with age, although the magnitude of association differed from LPFC (the strongest) to Cd (the weakest). Larger lateral PFC was associated with better performance on the mirror drawing task, and this link was stronger in the older participants and was strengthened at the later stages of learning. Larger caudate was related to better performance, especially at later learning, among men, but among women the link was evident only during early learning. Thus, mirror-drawing represents a task that, despite its visual-spatial nature, favors women, and may exhibit sexually dimorphic brain substrates.