Background: This study aims to evaluate sinistral portal hypertension (SPH) development and its clinical impact on the long-term outcomes of patients with pancreatic cancer who underwent surgical resection with splenic vein (SV) ligation. Methods: Data from 94 consecutive patients who underwent pancreatoduodenectomy (PD) with vascular resection for pancreatic cancer from 2008 to 2019 were retrospectively collected. The patients were divided into two groups according to whether the SV was preserved or ligated during the surgery. Their computed tomography images were serially reviewed (preoperative, 6-, 12-, and 24-months postoperative) with clinical parameters. The degree of variceal formation (variceal score) and splenomegaly were assessed, and the oncologic outcomes were compared between the two groups. Variceal score in the SV ligation group was significantly higher than that in the SV saving group at the same postoperative periods (SV saving vs. ligation: 12 months, 0.9 ± 1.3 vs. 3.5 ± 2.2, p < 0.001; 24 months, 1.4 ± 1.8 vs. 4.0 ± 3.4, p = 0.009). Clinically relevant variceal bleeding was noted in one patient from the SV ligation group (SV saving vs. ligation: 0.0% vs. 3.1%, p = 0.953). In survival analysis, there was no significant difference between the two groups (DFS; SV saving vs. ligation: 13.0 (11.1–14.9) months vs. 13.0 (10.4–15.6) months, p = 0.969, OS; SV saving vs. ligation: 35.0 (19.9–50.1) months vs. 27.0 (11.6–42.4) months, p = 0.417). Although SV ligation induced SPH during PD for pancreatic cancer, it did not lead to clinically significant long-term complications. In addition, it did not impact the long-term survival of patients with resected pancreatic head cancer.