ABSTRACT Background: The study examines substance use rates and their relationship with significant depressive symptoms and satisfaction with life among commercial motorcyclists. Methods: Participants were assessed with Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), PHQ-9, and Satisfaction with life scales (SWLS). The odds of developing depression were calculated for each substance use variable using chi-square. The relationship between substance use variables and SWLS was explored using independent t-test. A p-value of 0.05 or below was adjudged significant. Results: The lifetime and current prevalence of any substance use was 61.0% (95% CI = 56.3–65.3) and 53.7 (49.0–58.4) respectively. Alcohol was the commonest substance used, followed by cigarettes, tramadol, and cannabis in that order. Twenty-six percent had significant depressive symptoms mostly in the mild form. Participants with a history of lifetime and current use of any substance, lifetime, and current use of alcohol significantly had higher odds of experiencing significant depressive symptoms. No significant association between substance use variables and satisfaction with life scores. Conclusion: Findings show a high rate of substance use among commercial motorcyclists, even above the national average, with most being dissatisfied with life. Effort at reducing substance use and misuse may go a long way in reducing road traffic accidents, psychiatric morbidities and improving overall wellbeing.