Background: The causes of death following colorectal resection remain poorly explored. Few studies have addressed whether early post-operative mortality is predominantly caused by a patient's medical co-morbidities, or from factors pertaining to the presenting surgical disease process itself. This study analyses data from the Queensland audit of surgical mortality (QASM) to report the causes of in-hospital death following colorectal resection, identifies whether these were due to either medical or surgical factors, and determines the patient characteristics associated with a medical cause of death. Methods: Through analysis of QASM Surgical Case Forms, the causes of in-hospital death were determined in 750 patients who died in Queensland following colorectal resection between January 2010 and December 2020. Deaths were attributed to a specific medical or surgical cause, with multivariate analysis used to identify independent risk factors associated with a medical cause of death. Results: In total, 395 patients (52.7%) died due to surgical causes and 355 (47.3%) died due to medical causes. Respiratory co-morbidities (OR 1.832, 95% CI: 1.267–2.650), advanced malignancy (OR 1.814, 95% CI: 1.262–2.607), neurological co-morbidities (OR 1.794, 95% CI: 1.168–2.757) and advanced age (OR 1.430, 95% CI: 1.013–2.017) were independent risk factors associated with increased risk of a medical cause of death. Conclusion: Even in the absence of complicating surgical factors, a significant number of patients died in hospital following colorectal resection due to their underlying co-morbidities. Multi-disciplinary models of care which allow for the early recognition and treatment of medical complications may reduce post-operative mortality in these patients.