Identifying risk factors of poor self-rated health during adolescence is critical for the subsequent health status. The aim of this study was to investigate the most important determinants of self-rated health (SRH) in Iranian adolescents. This was a population-based cross-sectional study recruiting 605 adolescents in Isfahan, Iran. Simple random sampling method was employed. Multivariable linear regression model was utilized for determining the adjusted beta coefficient for health literacy (HL) and the study main confounders. The SRH of 93.2% of participants was satisfied or very satisfied. The majority of participants had moderate or high levels of HL (94.7%). Based on the standardized linear regression coefficients, HL was the most important correlates of SRH followed by happiness and loneliness, respectively. The mean of SRH in those with high HL, on average, was 0.48 units better than those with low HL (95% CI 0.23, 0.72), P < 0.001). We also found that happiness and satisfaction in child-parent relationship were positively correlated with SRH. Inversely, the history of passive smoking, loneliness and higher values of BMI significantly decreased the SRH in adolescents. We demonstrated health literacy, happiness and loneliness as the most important correlates of SRH. Considering the central role of adolescence on later health, the findings of current study imply that adolescence health promotion strategies, beside the formerly well-demonstrated factors, will best be targeted on health literacy to impact the general health positively.