The objective of the study was to examine the relationship and impact of comorbidity, pain, and function on quality of life in people aged 50-65 with upper extremity musculoskeletal disorders (UED), controlling for sex, occupational status, and age. This was a cross-sectional study. We performed hierarchical linear regression models to assess the extent that comorbidity and injury-related pain and disability affected overall health-related quality of life measured by the SF-36. We included 956 patients, of whom 601 were female. Physical and mental disability were associated significantly with lower levels of UE functional capacity (effect <sub>physical health </sub>= 0.24, SE = 0.10, <i>P</i> < 0.001; effect<sub> mental health</sub> = 0.17, SE = 0.09, <i>P</i> < 0.05). Comorbidity, pain, and occupational status have indirect relationships with UED, such that greater pain, a larger burden of comorbid health conditions, and less participation in the workforce, is associated with poorer physical and mental health. Mobility is key in promoting health and quality of life while contributing towards a successful transition into retirement.