Over the past decade, the practice of self-medication with anti-malarial drugs is becoming a major health concern specifically in the developing countries. A study has shown critical attention is needed to address this challenge since self-medication with anti-malarial drugs has been associated with increased morbidity and mortality due to malaria epidemic. This study aimed at exploring the factors influencing Urban district residents toward self-medication practice for anti-malarial drugs in Zanzibar. However, it was guided by the following specific objectives namely; (i) to explore the availability of anti-malarial drugs, (ii) to assess the level of knowledge on the consequences associated with self-medication (iii) to assess the economic influences on the practice of self-medication and (V) to assess the level of accessibility of anti-malarial drugs. A cross sectional descriptive study design was preferred. Both qualitative and quantitative approaches were used to collect data. The study was conducted in Urban district in Zanzibar. A total sample of 384 respondents was enrolled in the study. Purposive, convenient and simple random sampling techniques were used to select study participants. The data were collected by using questionnaire interviews, focus group discussions and documentary review. Quantitative data were analyzed by using Microsoft excel whereas qualitative data were analyzed manually. The studies found that, majority (75%) of the respondents were knowledgeable about the malaria in terms of sign, symptoms and treatment. The anti-malarial drugs were reported to be more in the government owned health facilities. Majority (58%) of the respondents indicated to be aware on the adverse effects associated with the practice of self-medication. Affordability of anti-malarial drugs was reported by the majority of the respondents and anti-malarial drugs were reported to be easily accessible. The study concluded that, the practice of self-medication with anti-malarial drugs is very common among the residence of Urban district. However, even though self-medication is common, majority of the population sought tested their blood sample before treating themselves.