Students, who are trying to complete academic activities in an educational environment, are objected to academic stress. Research results indicated that this stress can be reduced by the individual and psychosocial resources of them. So, this study aimed to determine the mediating role of grit and academic self-efficacy in the relationship between students' psychological need satisfaction and academic stress. The research was conducted on 967 college students who are studying at education, theology, and medical education faculty. We used serial mediation analysis to determine the mediator effect. Results demonstrated that there are statistically significant positive relationships between autonomy, competence, and relatedness, which are the components of psychological need satisfaction, grit, and academic self-efficacy, and negative relationships between academic stress. Mediation analysis results showed that the serial mediator effect of grit and academic self-efficacy was statistically significant in the relationship between autonomy, competence, relatedness, and academic stress. The research findings were interpreted according to the self-determination theory and positive psychology literature.