The misuse and abuse of substance by in-school adolescents has become a global issue and Nigeria is not exempted. The purpose of this study was to investigate the influence of substance abuse on psycho-social behaviour and academic performance of senior secondary school students in Ilorin Metropolis. Two research questions and two research hypotheses were answered and tested at 0.05 level of significance. The sample for the study comprised 220 SS1-3 students. The data collected were analyzed using mean, percentage and PPMC. One of the findings showed that there was a significant relationship between substance abuse and academic performance of in-school adolescents. It was also found that there is a significant relationship between substance abuse and psycho-social behaviour of in-school adolescents in Ilorin Metropolis. Based on the findings, it was recommended that; Kwara State ministry of health should make it more compulsory that drugs must be bought with doctor’s prescription either from the pharmacy shops or patent medicine stores. A task force should also be put in place to arrest and prosecute all mobile drug sellers on the road sides, market places etc
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