Key PointsQuestionAmong patients seeking musculoskeletal care, are improvements in physical function and pain interference associated with meaningful changes in symptoms of anxiety and depression?FindingsIn this cohort study of 11 236 US adults seeking musculoskeletal care, improvement by 2.3 population-level standard deviations (SD) or more on PROMIS Physical Function or 1.2 SD or more on PROMIS Pain Interference were required for any association with meaningful improvement in anxiety symptoms. Improvements in physical function and pain interference were not associated with meaningfully improved depression symptoms.MeaningThese results suggest that clinicians and patients cannot assume that exclusively addressing the physical aspect of a musculoskeletal condition will improve symptoms of depression or potentially even anxiety.