Little is known about the impact of substance use and psychiatric comorbidities on the management and outcomes of medical inpatients. This study explores the influence of psychiatric comorbidities, and substance use (tobacco, alcohol, and cannabis) on the length of hospital stay (LOS), Health-Related Quality of Life (HRQoL), and functioning in 800 medical inpatients at a high-complexity academic hospital. Multivariate analyses demonstrated that psychiatric comorbidities were associated with reduced HRQoL (β = −0.050, p-value = 0.017), and impaired functioning (β = 3.4, p-value <0.001). High-risk tobacco, alcohol, and cannabis use, according to the ASSIST were independently associated with impaired functioning. High-risk alcohol use was furthermore associated with longer stays (RR = 1.5, p-value <0.001). Female gender was associated with poorer HRQoL and functioning outcomes but with shorter LOS. These findings underscore the necessity of integrated mental health care within medical settings and emphasize the importance of a comprehensive approach considering psychiatric comorbidities, substance use, and gender perspective.