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Background: Students of higher educational institution are at higher risk of substance abuse. Currently, substance abuse is one of the most burning public health problems in Ethiopia. Again, the increasing rate of university students who take drugs, the scarcity of rehabilitation and treatment program on substance abuse threatens the present and future image of Ethiopia. Although it has been known that this public health problem is a pressing issue, the real extent and magnitude of the drug abuse is not yet properly explored. Only little research is done so far. Objective: This study aims at assessing the magnitude of Mekelle University students' practice of psychoactive substance abuse and their intention to stop. Methodology: Across sectional study design using mixed research method was employed (Quantitative, qualitative) during April 2011. After stratifying for batch and sex, simple random sampling (lottery) was used to select 662 students. Snowball sampling technique also was conducted. Data were gathered by annonymous self administer questionnaire. EPI Info version 3.5.1 and SPSS version 16.0 were used for cleaning and analysis. Binary and multiple logistic regressions were used to describe and associate the relevant variables. OpenCode 3.6 was used to manage qualitative data. Finally; thematic analysis was used to analize the data. CAGE-AID was used to measure substance abuse. Result: The response rate was 90.8%. Most 68% of the respondents were male. The magnitute of substance abuse was [95%CI: 20.1 (17.07, 23.48)]. The commonly abused substances were alcohol [95%CI: 16.6 (13.82, 19.78)] followed by khat 14.8(12.14-17.82) and cigarette and cannabis each were abused [95%CI: 8.8 (6.743, 11.29)]. It has also been identified that substances abuse in males [AOR, 95% CI; 2.214 (1.071, 4.575)] were two times higher than female respondents. In addition, those who started to abuse substance through peer pressure [AOR, 95% CI 14.931 (6.824, 32.668)] were 15 times more likely to abuse substances as compared to those who did not. In contrast, the study showed that students from Law and Governance [AOR, 95% CI .127 (.048, .335)] was less likely to abuse substances. Furthermore, proportion of intention to stop among abusers was 49.6%. Conclusion and Recommendation: From this finding, it is possible to conclude that, substance abuse is an urgent problem among undergraduate university students; however, their intention to stop is high. Sex, religion, field of study, reason to start and initiation time are statistically significant factors. Generally, from this study suggests that further work is urgently needed; to design suitable policies, culturally and psychologically appropriate intervention packages. Key words: Psychoactive substance abuse, Intention to stop, Mekelle University