Purpose: Despite repetitive activities and the frequency of high workload for municipal solid waste (MSW) collectors, the risks of work-related stress on upper extremity pain are inconclusive. The objective of this study is to assess the moderation and mediation effect of effort–reward imbalance (ERI) and over-commitment (OC) on upper back and hand/wrist disorders in MSW collectors. Methods: A cross-sectional study was conducted with MSW collectors from two cities in Taiwan. Each participant was asked to anonymously fill out a structured questionnaire. Work-related stress, including ERI and OC, was assessed by a Chinese version of the Job Content Questionnaire (C-JCL). Upper back and hand/wrist disorders were assessed using the Nordic musculoskeletal ques-tionnaire. Multivariate analysis was used to assess moderation and mediation effect of OC and ERI on upper extremity pain. Results: The moderation effect of ERI and OC on upper back and hand/wrist disorders in MSW collectors was found. Disorders were higher in the group with both ERI ≥1 and high OC (OR (odds ratio) = 3.25 and OR = 3.00) than in the group with ERI ≥1 and low OC (OR = 2.66 and OR = 1.87) and in the ERI <1 and high OC group (OR = 2.27 and OR = 1.26). Synergy indexes were 0.77 and 1.77, respectively. Using multivariate analysis after adjusting for covariates, the mediation effect of OC was significant for the association between ERI and upper back and hand/wrist pains. The indirect effects of OC for upper back and hand/wrist pains accounted for 35% and 42%, respectively, and OC appears to mediate the relationship between ERI and upper back and hand/wrist disorders in MSW collectors. Conclusion: Work-related stress measured ERI and OC may play a role in moderating and mediating effects on upper extremity pain. Encouraging provisions of work modification and stress management is needed to mitigate the occurrence of upper extremities pain in MSW collectors.