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This study examines how self-esteem and substance use impact depressionamong undergraduates at the Federal University of Lafia, Nigeria. Three hundred and ninety(390) participants with ages ranging from 19-25 years (Mean= 18.779; SD=11.42) wereselected using a simple random sampling technique. A survey research method was adoptedfor the study. Rosenberg’s self-esteem scale, Substance use questionnaire, and Beck’sdepression inventory were used to collect data. Linear regression was used to analysehypotheses one and two, and multiple regression was used to analyse hypothesis three. Findingsindicated that self-esteem significantly influenced depression among undergraduate studentsof the Federal University of Lafia (R = 0.863 = R2 = 0.547 (F (1,389) = 192.192, t = 14.170, p< .05). Also, it shows that substance use significantly influenced depression amongundergraduate students of Federal University of Lafia (R = 0.536 = R2 = 0.213 (F (1,389) =63.820, t = 4.711, p < .05). Similarly, the results revealed that self-esteem and substance usejointly influenced depression among undergraduate students of Federal University of Lafia (R= 0.724 = R2 = .520 (F (2, 388) = 107.544, t = -5.087, p < .05). It was recommended that;University management should ensure the availability of mental health resources and supportservices for students. This could include counselling services, workshops on self-esteemmanagement and well-being, and access to mental health professionals. There should be regularassessment of the mental health and well-being of students through surveys or confidentialfeedback mechanisms. This can help identify individuals who may be at risk of depression andenable targeted interventions or support. Substance use tests should be done regularly in orderto checkmate the illegal use of substances by students.