Abstract Background Self-medication is defined as using medicinal products to treat the disorders or symptoms diagnosed by oneself. Although informed self-medication is one of the ways to reduce health care costs, inappropriate self-treatment can pose various risks including drug side effects, recurrence of symptoms, drug resistance, etc. The purpose of this study was to investigate the knowledge, attitude, and practice of pharmacy and medical students toward self-medication. Methods This study was conducted in Zabol University of Medical Sciences in 2018. Overall, 170 pharmacy and medical students were included. A three-part researcher-made questionnaire was designed to address the students’ knowledge, attitude, and practice. Statistical analysis was performed in SPSS 25 software. Results According to the results, 97 (57.1%) students had carried out self-medication within the past 6 months. Overall, the students self-medicated on average 4.2 ± 2.9 times per year. Self-medication was more common in male students (65.4%, P = 0.043). Cold was the most common ailment treated with self-medication (93.2%), and antibiotics (74.4%) were the most commonly used drugs. The primary information sources used by the students were their previous prescriptions (47.4%). Pharmacy students had a higher level of drug information ( P < 0.001). There was a statistically significant association between the level of drug information and the tendency for self-medication ( P = 0.005). Disease recurrence was the most common negative complication of self-medication. Conclusion There is a need to educate pharmacy and medical students regarding self-medication and its side effects. The high prevalence of self-medication and the overuse of antibiotics can pose a significant risk of drug resistance.