Depression affects approximately 350 million individuals globally and is the leading cause of disability. Depression among nursing students is an ongoing issue, yet little is known about the relationship between depression and its risk factors among nursing students in Saudi Arabia. The purpose of this study was to determine the prevalence of depression among a cohort of Saudi nursing students and to explore the risk factors associated with depression in this group. A cross-sectional design was employed for this study, which was conducted by the nursing faculty at King Saud University in Riyadh, Saudi Arabia. The researcher sampled 330 nursing students, with 252 students (a 76.3% response rate) randomly selected by the academic advising unit in the nursing college between January and February 2023. The participants completed an online survey based on the Arabic version of the Center for Epidemiologic Studies Depression Scale. The data were analyzed using univariate analysis and backward multi-variable logistic regression. The findings revealed that 65.1% of the participants scored 16 or above on the depression scale, indicating high levels of depressive symptoms. Univariate analysis identified several significant risk factors for depression, including sex (OR, 0.29; 95% CI, 0.16-0.51; p < 0.001), academic pressure (OR, 5.87; 95% CI, 2.04-16.84; p < 0.001), interpersonal relationships (evaluated by balance and harmony in thoughts, emotions, behavior, and interactions with others; categorized as good/fair or poor), and the relationship with the father, which were strongly associated with the presence of depression symptoms. Backward multi-variable logistic regression analysis further revealed that being male, experiencing reduced academic pressure, having stronger father-son relationships, and maintaining positive interpersonal relationships were significantly associated with decreased levels of depression (ORs ranged from 0.25 to 3.94). These findings highlight the need for family and school-based prevention interventions to help nursing students in college avoid depression.