OBJECTIVE: Depression is commonly linked to cancer and may negatively impact patient outcomes; however, the influence of antidepressants on surgical outcomes remains unclear. We sought to evaluate the role of antidepressants among patients with gastrointestinal cancer and comorbid depression undergoing surgical resection. METHODS: Patients diagnosed with hepatobiliary, pancreatic, and colorectal cancers (2008-2019) were identified within SEER-Medicare. Comorbid depression, within 12 months before or after a cancer diagnosis, and antidepressant prescriptions were assessed. An "ideal" postoperative textbook outcome required no complications, prolonged stay, 90-day readmission, or 90-day mortality. Hospitalization and post-discharge expenditures were also assessed. RESULTS: Among 32,726 cancer patients (hepatobiliary: 2313, 7%; pancreatic: 2583, 8%; colorectal: 27,830, 85%), 1731 (5.3%) had documented depression (478 treated vs. 1253 untreated with antidepressant medications). Patients were more likely to receive treatment for depression if they were female (treated: 71% vs. untreated: 68%), White (treated: 88% vs. untreated: 80%), and had lower comorbidity burden (treated: 65% vs. untreated: 54%) (all p < 0.001). Patients with depression, both treated and untreated, had worse postoperative outcomes. Preoperative treatment with antidepressants decreased the effect of depression on adverse outcomes as patients with untreated depression were more likely to experience complications, prolonged stay, readmission, and mortality (all p < 0.001). Patients with untreated depression incurred higher in-hospital and 90-day post-discharge expenditures (no depression: $17,551; treated: $22,086 [7.3% increase]; untreated: $24,897 [10.2% increase]; p < 0.001). CONCLUSIONS: Depression reduced the likelihood to achieve optimal postoperative outcomes, yet antidepressant treatment preoperatively mitigated the size of these effects. Screening for depression and initiating appropriate therapy may enhance outcomes.