There exists a link between irritable bowel syndrome (IBS) and depression. Similarly, chronic depression is known to increase the risk of cancer in general. In this population-based analysis, we investigated the prevalence and the odds of colorectal cancer (CRC) in young-depressed patients with IBS. To investigate the relationship between IBS and CRC in young, depressed patients using a nationally representative United States inpatient sample. The 2019 National Inpatient Sample was used to identify young (18-44 years) patients admitted with comorbid depression in the presence vs absence of IBS using relevant International Classification of Diseases, Tenth Revision, Clinical Modification codes. Primary endpoint was the prevalence and odds of CRC in age matched (1:1) young-depressed cohort hospitalized with IBS (IBS+) vs without IBS (IBS-). Multivariable regression analysis was performed adjusting for potential confounders. Age-matched (1:1) young-depressed IBS+ (83.9% females, median age 36 years) and IBS- (65.8% females, median age 36 years) cohorts consisted of 14370 patients in each group. IBS+ cohort had higher rates of hypertension, uncomplicated diabetes, hyperlipidemia, obesity, peripheral vascular disease, chronic obstructive pulmonary disease, hypothyroidism, prior stroke, prior venous thromboembolism, anxiety, bipolar disorder, and borderline personality disorder (P < 0.005) vs the IBS- cohort. However, prior myocardial infarction, acquired immunodeficiency syndrome, dementia, smoking, alcohol abuse, and drug abuse (P < 0.005) are high in IBS- cohort. The rate of CRC was comparable in both cohorts [IBS+ n = 25 (0.17%) vs IBS- n = 35 (0.24%)]. Compared to the IBS- cohort, the odds ratio (OR) of developing CRC was not significantly higher [OR 0.71, 95% confidence interval (CI) 0.23-2.25)] in IBS+ cohort. Also, adjusting for baseline sociodemographic and hospital characteristics and relevant comorbidities, the OR was found to be non-significant (OR 0.89, 95%CI 0.21-3.83). This nationwide propensity-matched analysis revealed comparable prevalence and risk of CRC in young-depressed patients with vs without IBS. Future large-scale prospective studies are needed to evaluate the long-term effects of depression and its treatment on CRC risk and outcomes in IBS patients.