Background: Clinical deterioration, defined as end-organ dysfunction following surgery, is a devastating, yet potentially preventable set of complications, usually occurring after an inciting event. The extent to which deterioration occurs post-discharge after major gastrointestinal cancer surgeries is unknown. Our objectives were to (1) evaluate the incidence of post-discharge deterioration (PDD), (2) characterize the events surrounding PDD, and (3) identify factors associated with PDD. Methods: Patients who underwent gastrointestinal resection for cancer were identified from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Data File (2016-2019). Clinical deterioration was measured as a composite event consisting of respiratory failure, acute renal failure, cardiac arrest, or septic shock. Factors associated with PDD were evaluated using multivariable logistic regression. Results: Of 121,458 patients, 3,947 (3.3%) experienced clinical deterioration, with 19.1% occurring post-discharge. The median time to PDD from discharge was 8 days (IQR 4-13 days). Among patients who developed PDD, 58.9% had a previously diagnosed post-discharge complication, most commonly surgical site infection (38.2%), pneumonia (9.9%), and venous thromboembolism (5.4%). PDD was associated with older age, male sex, medical comorbidities, dependent functional status, longer operative time, transfusion, and discharge to a facility (all p < 0.05). Patients who underwent esophagectomy (OR 2.08 [95%CI, 1.39-3.10]) or pancreatectomy (OR 1.36 [95%CI, 1.07-1.74]) had significantly higher odds of developing PDD compared to patients who underwent colectomy. Conclusions: Post-discharge deterioration after major cancer surgeries commonly occurred after other potentially treatable post-discharge complications. Efforts should focus on improving post-discharge monitoring and timely and effective management of post-discharge complications to arrest their progression to post-discharge deterioration and mortality.