Background: Sub-optimal health status (SHS) and unhealthy lifestyle among college students have become a major focus for research on public health worldwide. Hence, this study was designed to assess the effects of socio-cultural factors on medical college students' self-rated health status (SRH) and health-promoting lifestyles (HPL) in Eritrea.Methods: A descriptive cross-sectional study was conducted at Orotta School of Medicine (OSM), using a self-administered questionnaire. Data was collected from all medical students who had fulfilled the inclusion criteria using Sub-Optimal Health Measurement Scale (SHMS V1.0) and Health-Promoting Lifestyle Profile-II (HPLP-II) scale questionnaires. Independent samples t-test, ANOVA, Chi-square test, Pearson's correlation coefficient and Binary multivariate logistic regression were performed. Data analysis was undertaken using SPSS version 22.Results: The overall SRH was significantly higher among college students with BMI of 25 to 29.9 (M=88.23, SD=6.28) as compared to <18.5 (p=0.027) and 18.5 to 24.9 (p=0.027). Moreover, physiological subscale of SRH was significantly related to gender (M males= 88.96 Vs M females= 85.41, p=0.001) and monthly stipend (M income = 89.52 Vs M no-income = 87.28, p=0.040). On the other hand, physical activity of HPL was found to vary by gender (M males= 2.12 Vs M females=1.87, p=0.005) and alcohol consumption (M drinkers= 2.22 Vs M non-drinkers = 1.99, p=0.016). Nutrition differences of HPL were observed in BMI of 25 to 29.9 (M =2.40, p=0.028), internship students (M=2.15, p=0.027), and monthly income (M=2.11, p=0.029). The overall SRH was significantly correlated with the overall HPL (r=0.493, p<0.001). In-addition, students who had good and excellent HPL had self-rated themselves as almost five times (AOR=4.97, 95% CI: 1.28, 19.32), and were 3.73 times (AOR=3.73, 95% CI: 1.09, 12.80) healthier than those who had poor HPL, respectively.Conclusions: Based on our study, gender, BMI and monthly stipend play a major role in the SRH whereas gender, alcohol consumption, BMI, study year and monthly stipend play a major role in the HPL. Moreover, there was a significant correlation between SRH and HPL in this study. Therefore, our findings provide evidence that support the role of socio-cultural influences' on SRH and HPL of medical students.