Handedness has long been tied to personality, but detailed explanations for the association are lacking. Importantly for purposes of theory development, measures of approach and withdrawal associated with Big Five personality traits have also been traced back to activity in brain areas that relate to handedness. Specifically, increased right-hemisphere frontal activity appears to be linked to both withdrawal motivation and left/inconsistent-handedness, while increased left-hemisphere frontal activity is associated with approach motivation and right/consistent-handedness. Cerebral motivational asymmetries therefore present one plausible mechanism by which approach and withdrawal motivation could mediate the relationship between handedness and personality. We tested this possibility in a large online study (N = 499) in which participants completed multiple survey measures. Results indicated that approach/withdrawal motivation partially accounts for relationships between handedness and personality.