This study examined the relationships among personality traits, coping efficacy, and academic stress in medical and non-medical students in South Korea, and investigated the mediating effect of coping efficacy in the relationship between personality traits and academic stress. The study group comprised 210 medical students and 175 non-medical students. They were asked to rate their personality traits, coping efficacy, and academic stress. The data were analyzed using IBM SPSS ver. 26.0 (IBM Corp., Armonk, NY, USA) and AMOS ver. 26.0 (IBM Corp.). Medical students scored higher for examination stress and lower for extroversion than non-medical students. In both groups, extroversion and conscientiousness positively affected coping efficacy, while neuroticism influenced it negatively. Neuroticism directly influenced all types of academic stress in both groups, while extroversion and conscientiousness only had direct effects on examination stress among medical students. Coping efficacy mediated the associations between personality traits and academic stress, except for the relationship between neuroticism and grade stress among medical students. The study indicates that coping efficacy had a significant effect on relieving academic stress among students with higher scores for extroversion and conscientiousness. Efforts should be made to decrease neuroticism to lower academic stress, as the relationship between neuroticism and academic stress is not directly influenced by coping efficacy. The implications of these results are discussed regarding a consultation system for students, especially those in medical school.