Variations in the cross-sectional properties of long bones are used to reconstruct the activity of human groups and differences in their respective habitual behaviors. Knowledge of what factors influence bone structure in Homo sapiens and Neandertals is still insufficient thus, this study investigated which biological and environmental variables influence variations in the femoral robusticity indicator of these two species. The sample consisted of 13 adult Neandertals from the Middle Paleolithic and 1959 adult individuals of H. sapiens ranging chronologically from the Upper Paleolithic to recent times. The femoral biomechanical properties were derived from the European data set, the subject literature, and new CT scans. The material was tested using a Mantel test and statistical models. In the models, the polar moment of area (J) was the dependent variable; sex, age, chronological period, type of lifestyle, percentage of the cortical area (%CA), the ratio of second moment areas of inertia about the X and Y axes (Ix/Iy), and maximum slope of the terrain were independent covariates. The Mantel tests revealed spatial autocorrelation of the femoral index in H. sapiens but not in Neandertals. A generalized additive mixed model showed that sex, %CA, Ix/Iy, chronological period, and terrain significantly influenced variation in the robusticity indicator of H. sapiens femora. A linear mixed model revealed that none of the analyzed variables correlated with the femoral robusticity indicator of Neandertals. We did not confirm that the gradual decline in the femoral robusticity indicator of H. sapiens from the Middle Paleolithic to recent times is related to the type of lifestyle; however, it may be associated with lower levels of mechanical loading during adolescence. The lack of correlation between the analysed variables and the indicator of femoral robusticity in Neandertals may suggest that they needed a different level of mechanical stimulus to produce a morphological response in the long bone than H. sapiens .