Introduction: Globally, youths are at risk of engaging in drug abuse. In Uganda, the prevalence of drug abuse among youths is 70.1% which is a lot higher than that of East Africa which is approximated at 45.5%. The study examined the factors influencing drug abuse among the youth in Kisenyi slum of Kampala district. It specifically assessed the relationship between socio-cultural factors, economic factors, and individual factors on drug abuse among youth. Methods: The study adopted a cross-sectional survey design in which a quantitative data collection approach was applied. Questionnaires were used to collect data from 239 youths. Data was cleaned, coded and entered into SPSS software for analysis. The results generated were in the form of descriptive statistics, Pearson chi-square analyses and binary logistics regressions. Results: The study found that the following factors had a statistically significant relationship with drug abuse in Kisenyi slum; religious service attendance (AOR=0.12; 95%CI=0.02-0.68; p=0.03*), family structure (AOR=20.04; 95%CI= 1.75-29.66; p<0.001*), family member smoking cigarettes/tobacco (AOR=0.83; 95%CI= 0.21-3.35; p=0.001*), a friend who drinks alcohol (AOR=1.21; 95%CI= 0.50-2.95; p=0.050*), a friend who smokes cigarettes/tobacco (AOR=0.47; 95%CI= 0.06-3.75; p=0.003*), television watching (AOR=3.56; 95%CI= 1.19-10.71; p<0.001*), social media access (AOR=1.51; 95%CI= 0.51-4.42; p=0.002*), type of house lived in (AOR=3.64; 95%CI= 0.91-14.5; p<0.001*), source of livelihood (AOR=0.88; 95%CI= 0.06-13.39; p=0.014*), drug availability (AOR=0.18; 95%CI= 0.03-1.20; p=0.029*), cost of drugs (AOR=5.92; 95%CI= 1.81-19.40; p<0.001*), perceptions on drugs (AOR=0.70; 95%CI= 0.17-2.88; p=0.002*), and convenience in talking (AOR=1.41; 95%CI= 0.48-4.15; p=0.002*). Conclusion: It can be concluded that socio-cultural, economic and individual factors have a statistically significant influence on drug abuse among youths in Kisenyi Slum, Kampala district. The study recommends engagement of religious leaders to include drug abuse and its effects in their sermons, regular police patrols to remand street children, rolling out business, technical vocational education and training (BITVET) to provide skills to youths, support youth businesses with seed capital and identification of youth champions to sensitize youths on drug abuse, its dangers and how to overcome addiction.