This study aimed to investigate the prevalence of psychoactive substance use and associated behavioral risks among secondary school students in Tanzania.   The study adopted a qualitative research approach. Data generated from semi-structured interviews with Heads of school, focused group discussions with teachers and students and documentary reviews were subjected to thematic analysis. Credibility, dependability, confirmability and transferability were considered to ensure trustworthiness. Rights and welfare of research participants and subjects were considered by the researcher. The most commonly used psychoactive substances among secondary school students were marijuana (cannabis), cigarettes and alcohol. Peer pressure, the family environment, the availability of substances in students localities are some of factors that influenced students to use psychoactive substances. The study recommends that the government should take special priority in banning the use of cannabis, cigarettes and alcohol, especially among secondary school students in order to minimize the prevalence of the use of psychoactive substances among secondary school students. School management and government at large need to establish drug control and prevention clubs in secondary schools so as to equip students with the necessary skills of knowing to resist temptations related to the use of psychoactive substances.