This study aimed at investigating if there is any significant difference between gender, depression and drug abuse among senior secondary school students in Calabar, Cross River State, Nigeria. The survey design was adopted. The study population was 1002 students from three senior secondary schools. However, 20% of the population which is 200 students were sampled using simple random sampling to form the sample of the study, only 190 students completed the study, two instruments were adapted and used for data collection namely: Beck’s Depression Inventory (BDI) and Drug Abuse Screening Test (DAST). The data collected were analyzed using descriptive statistics and independent t-test. The study revealed that there is significant difference in depression between the male and female students. The female students were more depressed than the males. There is also a significant difference in the way the male and female students abuse drugs. The male students abuse drugs more than the females. The results were discussed and it was recommended that homes and schools should be made more friendly to avoid depression in students and all sources of illicit drugs should be blocked. Article visualizations: