Artificial selection for increased levels of voluntary activity in mice has resulted in differences in whole bone morphology. To study evolutionary adaptation and phenotypic plasticity of bone in response to increased levels of activity, we compared cross‐sectional geometry of the femoral mid‐shaft in 59 male and female mice from three lines: randomly bred controls, high‐runner mice (HR), and HR mice expressing the Mini‐Muscle (MM) phenotype. Half of each group was either allowed or denied wheel access for ten weeks. From histological sections, we measured several relevant biomechanical traits. Male and female mice generally followed similar trends, although female mice differed significantly in cross‐sectional area among lines while males did not. HR mice in both sexes had the thinnest cortical bone, the largest medullary diameters, and, consequently, the greatest resistance to torsional loads. MM male and female mice exhibited more elliptical femoral mid‐shafts (with males differing significantly), with greater resistances to torsion. We conclude that bone micro‐structure responds both evolutionarily and plastically to increased loading. Future studies will evaluate rates of bone growth resulting in the observed differences. Supported by NSF IOB‐0543429 to TG and NIH 1F32AR053008‐01 to KMM.