Introduction We asseSssed factors influencing the uptake of voluntary medical male circumcision (VMMC) among boda-boda riders aged 18–49 years in Hoima, western Uganda. Despite high levels of awareness about availability and benefits of VMMC, uptake was still low. Methods We employed the convergent parallel mixed methods design among boda-boda riders in Hoima district between August and September 2020. We administered a structured questionnaire to 316 boda-boda riders to determine factors associated with uptake of VMMC. We also conducted eight focus group discussions (FGDs) and six key informant interviews (KIIs) to explore perceptions of VMMC. To determine factors associated with VMMC, we conducted modified Poisson regression analysis at 5% level of significance. We identified sociocultural barriers and facilitators for VMMC using thematic content analysis. Results Uptake of VMMC was at 33.9% (95% CI 28.6–39.1) and was associated with higher level of education, adjusted prevalence ratio (APR) 1.63, (95% CI 1.12–2.40); concern about being away from work, APR 0.66 (95% CI 0.49–0.88); and the belief that VMMC does not diminish sexual performance, APR 1.78 (95% CI 1.08–2.9). Facilitators of uptake of VMMC were health education and awareness creation, improved penile hygiene, and perceived sexual functioning; and reduced chances of HIV and sexually transmitted infections (STIs). On the other hand, the barriers to uptake were fear of pain and compulsory HIV testing, healing duration, financial loss during the healing period, fear of sexual misbehavior after circumcision, interruption of God’s creation, and fear of loss of male fertility. Conclusion Although VMMC is largely perceived as protective against HIV and other STIs, deliberate measures using multiple strategies should be put in place to address the barriers to its uptake among this key population.