This study aimed to investigate the mediating effects of the positive and negative meaning appraisal of college-to-work transition and career adaptability on the relationship between intolerance uncertainty and career stress. The survey was conducted on 443 college students. The collected data was analyzed through the SPSS 25.0 program, and the mediating effects were verified using Process Macro and bootstrapping. The results of this study are as follows. First, the indirect effect of negative meaning appraisal of college-to-work transition on the relationship between intolerance uncertainty and career stress was significant. Second, career adaptability had an indirect effect on the relationship between intolerance uncertainty and career stress. Third, there were the multiple mediating effects of positive and negative meaning appraisal of college-to-work transition and career adaptability on the relationship between intolerance uncertainty and career stress. Based on the above findings, implications of this study and suggestions for future research were discussed.