This study sought to examine the effects of substance use and stress-induced cognitive impairment on anxiety and depression among college students. The data for this study came from a sample of 328 undergraduate students from a public university. The subjects in this study completed a 101-item self-administered questionnaire, which was part of a larger study on college stress. This study included not only students who are typically expected to seek help at the counseling centers, but it expanded to include self-reported cases of students who do not have documented problems of substance use or anxiety/depression. To address the main objective of this study, an eight-variable model was developed and tested for each of the two outcome variables: anxiety and depression. The results that emerged from this study show that both substance use and stress-induced cognitive impairment have a positive and a statistically significant effect on anxiety and depression in college students.