BACKGROUND: In the digital age, the relationship between social media use and mental health has gained significant attention. Problematic social media use can negatively affect mental health, while mental health literacy plays a crucial role in mitigating these effects. OBJECTIVE: This study aimed to explore the relationships between problematic social media use, mental health literacy, and their interaction with depression among nursing students. METHODS: A convenience sample of 628 nursing students from a university was selected. Participants completed questionnaires assessing social media use, mental health literacy, and depressive symptoms. The tools used included the PHQ-9, the Youth Mental Health Literacy Scale, and the Problematic Use of Mobile Social Media Scale. Multiple logistic regression was performed to examine associations. RESULTS: The average score for problematic social media use was 56.29 ± 16.22, with 159 students (24.84%) exhibiting problematic behaviors. The average depression score was 5.19 ± 5.32, with 296 students (46.25%) showing depressive symptoms. The average mental health literacy score was 82.46 ± 13.24, with 191 students (29.84%) demonstrating adequate literacy. Logistic regression analysis revealed that both problematic social media use and low mental health literacy were risk factors for depression, with additive and multiplicative interactions. Nursing students with both problematic social media use and low mental health literacy had the highest depression detection rate of 77.2% (88/114), with an odds ratio (OR) of 6.464. CONCLUSIONS: Depression is prevalent among nursing students. Problematic social media use and low mental health literacy are significant risk factors for depression, and their interaction significantly increases the risk. Reducing problematic social media use and improving mental health literacy can help prevent depression and other negative emotional states among nursing students.