Purpose: To determine if weight status modifies the relationship between motor skill (MS) performance and physical activity (PA) in preschoolers. Methods: Preschoolers ( N = 227, age 3–5 y) were recruited from 22 preschools. Preschoolers’ MS (locomotor, object control, and total MS) were assessed with the Children’s Activity and Movement in Preschool Study MS protocol. PA was measured by accelerometry. Mixed linear models were used to examine the relationship of MS performance and body mass index (BMI) z score to PA. Models were adjusted for age, race, sex, and parent education, with preschool as a random effect. Results: There was a significant correlation between MS performance and PA ( r = .14–.17, P < .05). A significant interaction was observed between BMI z score and object control,... and between BMI z score and total MS score on PA ( P = .03). Preschoolers with higher BMI z scores and high object control scores engaged in significantly ( P = .03) more PA than preschoolers with lower BMI z scores and high object control scores (PA = 15.04 min/h and 13.54 min/h, respectively). Similarly, preschoolers with higher BMI z scores and high total MS scores spent significantly ( P = .01) more time in PA compared with those with lower BMI z scores and high total MS scores (PA = 15.65 min/h and 13.91 min/h, respectively). Conclusion: Preschool children’s MS performance is positively correlated with PA, and BMI z score modified the relationship between MS performance and PA.