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Abstract ObjectivesTo use a mouse model to investigate the relationships among the components of the systemic robusticity hypothesis (SRH): voluntary exercise on wheels, spontaneous physical activity (SPA) in cages, growth hormones, and skeletal robusticity, especially cranial vault thickness (CVT). Materials and MethodsFifty female mice from lines artificially selected for high running (HR) and 50 from nonselected control (C) lines were housed in cages with (Active) or without wheels (Sedentary). Wheel running and SPA were monitored daily. The experiment began at 24–27 days of age and lasted 12 weeks. Food consumption was measured weekly. Mice were skeletonized and their interparietal, parietal, humerus, and femur were µCT scanned. Mean total thickness of the parietal and interparietal bones was determined, along with thickness of the cortical and diploe layers individually. Geometric cross‐sectional indicators of strength were calculated for the long bones. Blood samples were assayed for IGF‐1 and IGFBP‐3. ResultsPhysical activity differed significantly among groups, based both on linetype (C vs. HR) and activity (A vs. S). However, contrary to our predictions, the ratio of IGF‐1 to IGFBP‐3 was higher in C mice than in HR mice. Neither CVT nor postcranial robusticity was affected by linetype or activity, nor were most measures of CVT and postcranial robusticity significantly associated with one another. DiscussionOur results fail to provide support for the systemic robusticity hypothesis, suggesting it is important to rethink the long‐standing theory that increased CVT inHomo erectusreflects increased physical activity compared other hominin species.