Background <p>Nurses in under-resourced settings frequently report high levels of musculoskeletal (MSK) discomfort, which significantly affects their mental well-being. While workplace strain is well documented, the combined impact of physical burden and institutional neglect remains underexplored in these environments.</p> Aim <p>The study aims to examine the prevalence of MSK discomfort and its association with psychological well-being among nurses in under-resourced healthcare environments in Northeast India, and to explore the experiential and structural factors contributing to these occupational health risks.</p> Methods <p>A sequential mixed-methods study design was employed, following an explanatory approach. The study commenced with a survey to gather quantitative data. Quantitative data were collected from 216 nurses using the Extended Nordic Musculoskeletal Questionnaire (Extended-NMQ) and the WHO-5 Well-Being Index, the results of which informed the development of subsequent interview questions. Semi-structured interviews were then conducted with 11 nurses to capture experiential and structural factors. This structure enabled deeper contextual understanding and facilitated triangulation across data types.</p> Results <p>Among the participants, 47.2% reported experiencing lower back pain, followed by discomfort in the knees (27.3%) and upper back (25%). Higher levels of MSK discomfort were significantly associated with employment in the public sector and more than ten years of work experience. A strong negative correlation was observed between MSK discomfort and mental well-being. Thematic analysis revealed key stressors: physical depletion, emotional exhaustion, organizational apathy, and limited healthcare access. In response to these challenges, nurses often relied on self-management due to insufficient institutional support. Triangulated findings underscored how structural deficiencies intensified both physical and psychological strain among nurses.</p> Conclusions <p>There is an urgent need for evidence-based occupational health interventions to address ergonomic, psychosocial, and institutional challenges, particularly in low-resource healthcare settings, to safeguard the well-being of frontline nursing staff. This study offers novel understanding from a high-need yet under-researched geographic context, namely the northeastern states of India, bridging empirical gaps in MSK health literature through the integration of experiential and structural factors.</p> Clinical trial number <p>Not applicable.</p>