Background — Obesity is a condition caused by the interaction of complex factors, which include genetics and behavioral components, such as physical activity and diet. Obesity has a negative impact on physical performance, quality of life (QoL), and health-promoting lifestyle (HPL). The purpose of our study was to investigate the relationship of QoL and HPL with body mass index (BMI) in medical students of Southern Iran. Methods — This cross-sectional study was conducted in 2021 on 536 students in Southern Iran. Data collection was completed using standardized QoL and HPL questionnaires and anthropometric measurements. Data were analyzed by chi-squared test and one-way ANOVA, assuming significance level of p<0.05, using the IBM SPSS Statistics 21 software package. Results — The mean age of study participants was 21.33±2.03 years. Over 88% of them were female; 347 (64.7%) students had normal BMI and 189 (35.3%) had abnormal BMI. Among the dimensions of QoL were physical health (p=0.03), mental health (p<0.001) and general health (p=0.01). We revealed statistically significant differences in students with different BMI levels. Among the dimensions of HPL, stress management (p<0.001), physical activity (p<0.001) and nutrition (p<0.05) exhibited statistically significant differences in groups based on BMI. Conclusion — Based on the results of this study, we concluded that it is necessary to plan multiple interventions, especially in the form of continuous and short-term training courses, and to encourage medical students to pursue a healthy lifestyle, especially in terms of nutrition, physical activity and stress management.