Background: Activity breaks are an established way physical activity may be incorporated into the preschool day. The purpose of this study was to examine what factors influenced moderate to vigorous physical activity (MVPA) during a teacher-implemented classroom-based activity break (CBAB) in a Head Start population. Methods: Ten-minute CBAB was conducted over 2 days in a quasi-experimental design; 99 preschoolers (mean age 3.80 [0.65] y; 49.5% male) from a convenience sample participated. Accelerometers measured MVPA, fundamental motor skill competency was assessed using the Test of Gross Motor Development—second edition, and weight classification status used body mass index percentiles. Results: A significant, moderate regression was found (r = .328, P = .001) between fundamental motor skill and MVPA. There was no significant correlation between body mass index percentile and MVPA during the CBAB. In addition, the locomotor subscale was the best predictor for MVPA for children during the CBAB (r = .32, β = 0.82, P < .001). Conclusions: CBAB equally elicited MVPA for normal and overweight preschoolers. Fundamental motor skill competency was associated with MVPA during the CBAB; in particular, locomotor skills were the best predictor for physical activity. Structured activity opportunities that focus on locomotor skills may be a useful integration to prompt more MVPA in a preschool-age population.