Financial anxiety is a growing concern among healthcare workers globally, yet research on its psychological impact among health assistants in Nigeria remains limited. This mixed-methods study examined the relationships among perceived financial anxiety, coping strategies, and health-related quality of life (HRQoL) among health assistants at University College Hospital (UCH), Ibadan, Nigeria. A sequential explanatory mixed-methods design was employed. Quantitative data were collected from 255 health assistants using validated instruments: Perceived Financial Anxiety Scale (PFAS, α = 0.936), Brief-COPE (α = 0.864), and WHOQoL-BREF (α = 0.875). Confirmatory factor analysis (CFA) was performed on the PFAS. Regression analyses tested three hypotheses. Qualitative data were collected via 10 in-depth interviews and analyzed thematically. The three-factor PFAS model showed acceptable fit (χ²/df = 3.12, CFI = .872, SRMR = .062). Health assistants with higher financial anxiety reported significantly lower HRQoL (β = -0.319, p < .001, R² = .100). Avoidant coping was the only significant independent predictor of HRQoL among the coping styles (β = -.181, p = .009). Demographics jointly explained 12.1% of HRQoL variance; being divorced or widowed was associated with lower HRQoL, while holding a professional certificate was associated with higher HRQoL. Thematic analysis revealed themes of debt, basic needs struggles, avoidance coping, religious support, and suicidal ideation. Financial anxiety significantly reduces HRQoL among health assistants. Avoidant coping is maladaptive, while problem-focused coping alone does not robustly improve HRQoL. Organisational and policy interventions such as fair remuneration, financial wellness programmes, and mental health support are urgently needed.