Background: commercial drivers who abuse psychoactive substances may engage in criminal/violent behavior, risky sexual behavior, driving under the influence of a substance, rape, fighting, and robbery, or dispossessing commuters of their valuables. Aim: The present study aims to assess knowledge and factors related to the use of psychoactive substances among commercial vehicle drivers. Design: A descriptive correlation design was used. Setting: This study was conducted at four car stations. Sample: A multistage stratified sample of 285 commercial car drivers. Results: the present study reflects drivers' reports, 56.1% of drivers take power drinks, 35.1% and 16.1% of them take Marijuana and Cannabis. Also, 42.8% and 19.6% of them take sleeping pills such as phenobarbital and drink beer respectively. Conclusion: poor knowledge about psychoactive hazards and highly statistically significant differences between personal, and work-related data, types of psychoactive substances, reported reasons, and hazards knowledge. Recommendation: Organizing training programs for commercial drivers about psychoactive health hazards that cover different settings in Egypt.