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Mental health professionals (MHPs) play a pivotal role in enhancing treatment outcomes for drug-using populations and minimizing their harm to the public. In response to a gap in the literature, this study sought to (a) assess MHPs' attitudes about the use and abuse of substances and their perception of their role in tackling substance abuse and related disorders in Nigeria, (b) identify predictors of perception, and (c) explore regional variations in attitude. Based on the validated drug and drug users' problems perception questionnaire and the substance abuse attitude survey, a cross-sectional survey was conducted in a randomized sample of 292 MHPs practicing in neuropsychiatric hospitals and in the mental health departments of teaching hospitals from 4 geopolitical zones of Nigeria. A response rate of 81.1% was achieved. MHPs' attitude about substance use tended towards the non-permissive, stereotypical, and moralistic spectrum, and its role perception was distinctly defined. Educational attainment (O.R = 0.50, p = 0.030), work-motivation (O.R = 0.55, p < 0.0001), and role-support (O.R = 1.48, p < 0.0001) significantly predicted MHPs' role perception. The Kruskal-Wallis test showed that there were significant regional variations in the attitudes of multidisciplinary MHPs, H (3) 18.727, p < 0.0001. Step-down follow up analysis revealed that the distribution of attitude total score vary significantly between the south-southern and southwestern region (p< 0.001), the northeastern and southeastern region of the country (p < 0.028). To foster the rehabilitation of this population and its reintegration into mainstream society, a holistic approach toward the standardization of drug treatment is needed. It should take into account the cultural, religious, and ethnic differences predominating in different regions.