Substance abuse is a worldwide public health challenge with college youth being among those affected. An estimated 10-15 % of students in medical training institutions risk substance abuse in their lifetime as they are not immune to the predisposing factors associated with the abuse. The conduct and efficiency of medical training college (MTC) students as future healthcare professionals may be impacted negatively by substance abuse; consequently, the patients are at risk. In Kenya, substance abuse is prevalent among college youth though data on the factors associated substance abuse by students in MTCs are still unclear. South Nyanza, the study area lies within marijuana transit route along Kisii -Migori road from Tanzania to Nairobi, Kenya. The objective of the study was to determine the factors associated with substance abuse by students in MTCs in South Nyanza Region. Cross-sectional descriptive study design was used.