Long-haul truck drivers in Nigeria, particularly in logistics hubs like Port Harcourt, face prolonged driving hours, poor road conditions, vibration exposure, suboptimal cabin ergonomics, and irregular shifts, which contribute to work-related musculoskeletal disorders (WMSDs), chronic fatigue, and elevated road safety risks. This study investigated the prevalence, key occupational hazards, and potential intervention strategies for WMSDs and fatigue among Port Harcourt truck drivers. A mixed-methods cross-sectional study was conducted using multi-stage sampling among 380 active long-haul truck drivers recruited from major truck parks and loading points in Port Harcourt Data were collected via structured interviewer-administered questionnaires, including sociodemographic and occupational characteristics, the Standardized Nordic Musculoskeletal Questionnaire (NMQ) for WMSD prevalence and severity, the Fatigue Assessment Scale (FAS) for fatigue levels, an adapted ergonomic exposure checklist, and self-reported road traffic incidents. Semi-structured in-depth interviews (n = 25) were conducted to explore lived experiences, perceived hazards, and intervention suggestions. Quantitative data were analyzed using descriptive statistics, logistic regression, and correlation analyses; qualitative data were analyzed in a thematic manner. The participants were predominantly male (98.7%), with a mean age of 38.4 ± 9.2 years and a mean driving experience of 9.6 ± 6.3 years. Drivers reported an average of 12.8 ± 3.4 daily driving hours, with 70.0% exceeding 60 hours weekly. The 12-month prevalence of WMSD was 82.6%, with the lower back being the most affected (68.9%), followed by the neck (47.9%) and shoulders (45.0%); 54.1% of cases were moderate/severe, and 40.8% of cases were interfered with work. Significant fatigue (FAS ≥28) affected 70.0% of drivers (mean score 33.8 ± 8.1), which was strongly correlated with WMSDs (r = 0.65, p 60 h/week (OR 3.5), high fatigue (OR 4.6), high vibration exposure (OR 3.1), poor ergonomics (OR 2.9), and age >40 years (OR 2.1). Safety outcomes were concerning: 30.0% reported at least one accident and 55.8% experienced near-misses or lapses related to fatigue/pain in the past year. Drivers of trucks in Port Harcourt experience alarmingly high burdens of WMSDs and fatigue, driven by ergonomic deficiencies, prolonged hours, vibration, and inadequate rest, which substantially increase occupational health risks and road traffic incident likelihood. Urgent, context-specific interventions, such as improved truck cab ergonomics, mandatory rest regulations, vibration-dampening measures, fatigue monitoring, and policy enforcement, are essential to protect driver health, reduce preventable accidents, and enhance safety in Nigeria’s critical trucking sector