(1) Background: The rising prevalence of e-cigarette use among university students necessitates a comprehensive understanding of dependence levels and associated factors. This study investigates e-cigarette dependence among Jazan University students in Saudi Arabia. (2) Methods: With the use of a cross-sectional design, data were collected from 1187 students through an online survey from January to April 2024. Dependence levels were assessed using the Penn State Electronic Cigarette Dependence Index (PS-ECDI), and the Arabic version of the questionnaire was validated through pilot testing. Multivariable logistic regression analysis was employed to identify factors associated with e-cigarette dependence. (3) Results: The results indicated that among current e-cigarette users, 37.4% had low dependence, 34.4% had medium dependence, and 13.8% had high dependence. A significant proportion of current and ever users regarded e-cigarettes to be less harmful (50.6% and 44.4%, respectively) and less addictive (37.9% and 32.3%, respectively) than cigarettes. Significant factors influencing dependence included gender, with males showing higher odds of medium (AOR = 12.8, 95% CI: 3.4-47.6) and low dependence (AOR = 9.7, 95% CI: 2.5-37.3) compared to females. Longer duration of e-cigarette use (>2 years) was strongly associated with high dependence (AOR = 50, 95% CI: 7.7-324). Daily use and multiple quit attempts were also significant predictors of higher dependence levels. (4) Conclusions: These findings highlight the substantial e-cigarette dependence among university students and underscore the need for targeted interventions to address this growing public health concern.