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Purpose: The purpose of this study was to investigate the mediating effect of college adjustment on the relationship between self-leadership and career decision-making self-efficacy in first-year nursing students. Methods: This descriptive research involved 250 nursing freshmen at two local universities and analyzed data from the final 170 students. Descriptive statistics, the independent t-test, the Kruskal-Wallis test, the Mann-Whitney U test, the Pearson correlation coefficient and multiple regression were employed for data analysis. The mediating effect was assessed following Baron and Kenny’s three-step verification procedure, and the statistical significance of the mediating effect was determined by bootstrapping. Results: Academic adjustment (β=.24, p<.001) and institutional adjustment (β =.20, p=.004), sub-factors of college adjustment, were identified to have a partial mediating effect on the relationship between the subject's self-leadership and career decision-making self-efficacy (β=.47, p<.001). Conclusion: Enhancing the career decision-making self-efficacy of first-year nursing students could become more effective through the development of programs focused on career exploration and counseling, which include content to promote self-leadership and college adjustment (academic adjustment and institutional adjustment).