Objective <p>This study aimed to explore the relationship between mental health literacy, communication anxiety, and mobile phone dependence among first-year medical students.</p> Methods <p>This study adopted a cross-sectional design. A total of 547 valid questionnaires were included in the analysis. Mobile phone dependence, mental health literacy, and communication anxiety were assessed using the Smartphone Addiction Scale–Short Version (SAS-SV), Mental Health Literacy Questionnaire–Short Version for Adults (MHLq-SVa), and Interaction Anxiousness Scale (IAS), respectively. Spearman’s rank correlation and hierarchical regression analyses were conducted to examine the associations among mental health literacy, communication anxiety, and mobile phone dependence.</p> Results <p>Mobile phone dependence was identified in 64.9% of first-year college students. Univariate analysis showed that mobile phone dependence was significantly associated with communication anxiety and the duration of mobile phone use (<i>P</i> &lt; 0.001). Hierarchical regression analysis, after adjusting for demographic covariates, indicated that communication anxiety was significantly and positively associated with mobile phone dependence (<i>β</i> = 0.380, <i>P</i> &lt; 0.001). Additionally, monthly living expenses were significantly positively associated with mobile phone dependence (1000–1999 Yuan: <i>β</i> = 0.158, <i>P</i> = 0.016; ≥2000 Yuan: <i>β</i> = 0.181, <i>P</i> = 0.007). Conversely, mental health literacy was not significantly associated with mobile phone dependence (<i>β</i>=−0.027, <i>P</i> = 0.492).</p> Conclusion <p>Mobile phone dependence among first-year college students was associated with monthly living expenses and communication anxiety, whereas no significant association was found with mental health literacy. These findings suggest that communication anxiety may warrant greater attention than mental health literacy in future intervention research addressing mobile phone dependence in this population.</p>