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Background: Informal sewing workers are widely exposed to ergonomic and workload-related risks but remain largely excluded from formal occupational health protection, particularly in low- and middle-income countries. This study evaluated integrated physical and mental workload risks associated with WMSDs among informal sewing workers to develop contextually feasible preventive guidelines based on the Hierarchy of Ergonomic Control. Methods: A mixed-methods study was conducted among 150 informal sewing workers in Ubon Ratchathani Province, Thailand. Quantitative data were collected using a structured questionnaire, the Rapid Upper Limb Assessment (RULA), the Nordic Musculoskeletal Questionnaire (NMQ), and the NASA Task Load Index (NASA-TLX). Associations between sociodemographic characteristics, ergonomic risks, and WMSDs were analyzed using chi-square tests and correlation analysis. Qualitative data were obtained through a focus group discussion with key stakeholders to develop ergonomic control strategies guided by the HEC framework. Results: The majority of participants were female and middle-aged, with widespread exposure to high-risk ergonomic conditions, including prolonged sitting, repetitive tasks, and awkward postures. A high prevalence of WMSDs was observed, particularly in the neck, shoulders, and back. Younger workers and those with lower educational attainment experienced significantly higher ergonomic risk exposure and WMSD prevalence. NASA-TLX results indicated that physical demand and performance pressure were the main contributors to overall workload. Application of the HEC framework showed that elimination and substitution controls were the most effective strategies for reducing ergonomic risks, followed by engineering controls, while administrative measures and personal protective equipment were less effective. Conclusions: Informal sewing workers face substantial ergonomic and mental workload risks that contribute to a high burden of WMSDs. Prioritizing higher-order ergonomic controls, integrating workload management, and implementing community-based ergonomic interventions are essential to improving occupational health and reducing inequities among informal workers.