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Region-specific differences in age-related bone remodeling are known to exist. We therefore hypothesized that the decline in tissue-level strength and post-yield strain (PYS) with age is not uniform within the femur, but is driven by region-specific differences in porosity and composition. Four-point bending was conducted on anterior, posterior, medial, and lateral beams from male cadaveric femora (n = 33, 18-89 yrs of age). Mid-cortical porosity, composition, and mineralization were assessed using nano-computed tomography (nanoCT), Raman spectroscopy, and ashing assays. Traits between bones from young and elderly groups were compared, while multivariate analyses were used to identify traits that predicted strength and PYS at the regional level. We show that age-related decline in porosity and mechanical properties varied regionally, with highest positive slope of age vs. Log(porosity) found in posterior and anterior bone, and steepest negative slopes of age vs. strength and age vs. PYS found in anterior bone. Multivariate analyses show that Log(porosity) and/or Raman 1246/1269 ratio explained 46-51% of the variance in strength in anterior and posterior bone. Three out of five traits related to Log(porosity), mineral crystallinity, 1246/1269, mineral/matrix ratio, and/or hydroxyproline/proline (Hyp/Pro) ratio, explained 35-50% of the variance in PYS in anterior, posterior and lateral bones. Log(porosity) and Hyp/Pro ratio alone explained 13% and 19% of the variance in strength and PYS in medial bone, respectively. The predictive performance of multivariate analyses was negatively impacted by pooling data across all bone regions, underscoring the complexity of the femur and that the use of pooled analyses may obscure underlying region-specific differences.