Background: Immunotherapy has revolutionized the treatment landscape of many malignancies, but its therapeutic role in pancreatic cancer (PC) remains unclear. The objective of this study is to investigate the impact of immunotherapy on the overall survival of PC patients stratified by definitive surgery of the pancreas using the National Cancer Database (NCDB). Methods: Patients with pancreatic adenocarcinoma were identified from NCDB. Cox proportional hazard models were employed to assess the impact of immunotherapy on survival after being stratified by surgery and adjusted for age of diagnosis, race, sex, place of living, income, education, treatment facility type, insurance status, year of diagnosis, and treatment types such as chemotherapy and radiation therapy. Results: Of 252,280 patients who were analyzed, 214,632 (85.08%) had definitive surgery, and 37,638 (14.92%) did not get definitive surgery of the pancreas. In the surgery group, 351 (0.93%) received immunotherapy and 37,287 (99.07%) did not while in the no surgery group, 838 (0.39%) received immunotherapy and 213,804 (99.61%) did not. In the multivariable analysis, patients who received immunotherapy had significantly improved OS both in the no surgery group (HR: 0.886, CI: 0.655-0.714; P < 0.0001) and in the surgery group (HR: 0.846, CI: 0.738-0.971; P < 0.0001) compared to patients who did not receive immunotherapy. Treatment with chemotherapy plus immunotherapy was associated with significantly improved OS (HR: 0.871, CI: 0.784-0.967; P < 0.009) compared to chemotherapy without immunotherapy in the no surgery group, while it was not significant in the surgery group. Chemoradiation plus immunotherapy was associated with significantly improved OS (HR: 0.787, CI: 0.684-0.906; P < 0.0009) in the no surgery group and (HR: 0.799, CI: 0.681-0.938) in the surgery group compared to chemoradiation alone. Conclusions: In this study, the addition of immunotherapy to chemoradiation therapy was associated with significantly improved OS in PC patients with or without definitive surgery. The study warrants further future clinical trials of immunotherapy in PC.