Background: Occupational physical activity (OPA) is prevalent in the general population. However, its influence on the health status of manual workers is unclear. This study examined the impact of OPA on the health-related quality of life (HRQoL) of vocational-skilled workers (VSWs) in Nigeria. 
Materials and Methods: This cross-sectional study was conducted on 354 male VSWs from six cities in Osun State, Nigeria. VSWs were selected using a multistage sampling method. OPA level and HRQoL were assessed using items from the International Physical Activity Questionnaire-Long Form and the Short Form (SF-36) Health Status Questionnaire, respectively. High OPA was defined as >3000 MET-min/week. Data were analyzed using bivariate and multivariate statistics.   
Results: Participants’ mean age was 38.3±9.6 years, and 68.4% of the participants reported high OPA. As regards HRQoL, higher scores in physical functioning (PF) and physical composite summary (PCS) were found among the participants with high OPA. Amongst those with moderate OPA, higher scores were found in social functioning, mental health (MeH), and mental composite summary (MCS). Significant differences were found in role limitation due to physical health problems (t=0.55; p=0.002), bodily pain (BoP) (t=0.51; p=0.021), PCS (t=0.46; p=0.014), and MeH (t=0.27; p=0.026).  Additionally, VSWs with high OPA were less likely to have problems with BoP (OR=0.70, CI=0.52–0.95) and MCS (OR=0.53, CI=0.35–0.78), but were twice more likely to have good PCS (OR=2.25, CI=1.21–4.18).         
Conclusions: The OPA level of Nigerian VSWs was high with significant impact on the HRQoL. Interventions focusing on promoting OPA to improve HRQoL are recommended.