BACKGROUND AND AIM: The move towards Open and Distance Learning (ODL) has changed students' overall lives and perspectives in Bangladesh. This study aims to explore the psychological impact of ODL on Bangladeshi students, focusing on academic stress, social isolation, and self-efficacy as mediators. METHODS: A cross-sectional survey using a quantitative research design was used. University students in ODL programs were studied using a structured questionnaire of 320 respondents. A 7-item scale for ODL experience, Academic Stress Scale (ASS), UCLA Loneliness Scale, 6-item scale for self-efficacy, and Ryff's Psychological Well-Being Scale were used. Items for each scale were rated on a 5-point Likert scale that ranged from strongly disagree (1) to strongly agree (5). This study employed Structural Equation Modeling (SEM) to examine the construct relationships. The reliability, validity, and discriminant validity of the measures were assessed by Cronbach's Alpha, Composite Reliability (CR), Average Variance Extracted (AVE), and Fornell-Larcker Criterion. Path, mediation, and moderation analyses were additionally carried out to test the indirect effects of academic stress, social isolation, and self-efficacy. RESULTS: The findings demonstrate that ODL significantly predicted lower psychological well-being (β = -0.42) through an increase in academic stress (β = 0.49) and social isolation (β = 0.41). Stress and isolation are significant mediators of the relationship between ODL and well-being. Self-efficacy, however, moderated how well of an indicator ODL affected psychological health and acted to buffer the negative relationship between ODL and well-being (β = 0.09). CONCLUSION: Finally, the study revealed that ODL arrays come with many mental health challenges, increasing academic stress and social isolation among students, especially less self-affected individuals. Nevertheless, the results do highlight unique areas that institutions of higher learning can target to cope with these psychological factors to enhance students' online learning experiences.