Mesenteric approach is an artery‐first approach during pancreaticoduodenectomy (PD). In the present study, we evaluated clinical and oncological benefits of this procedure for pancreatic ductal adenocarcinoma (PDAC) of the pancreas head. Between 2000 and 2015, 237 consecutive PDAC patients underwent PD. Among them, 72 experienced the mesenteric approach (mesenteric group) and 165 the conventional approach (conventional group). A matched‐pairs group consisted of 116 patients (58 patients in each group) matched for age, gender, resectability status, and neoadjuvant therapy. Surgical and oncological outcomes were compared between the two groups in unmatched‐ and matched‐pair analyses. Intraoperative blood loss was lower in the mesenteric group than in the conventional group in both resectable PDAC (R‐PDAC) and borderline resectable PDAC (BR‐PDAC) on unmatched‐ and matched‐pairs analyses (R‐PDAC, unmatched: 312.5 vs 510 mL, P=.008; matched: 312.5 vs 501.5 mL, P=.023; BR‐PDAC, unmatched: 507.5 vs 935 mL, P<.001; matched: 507.5 vs 920 mL, P=.003). Negative surgical margins (R0) and overall survival (OS) rates in the mesenteric group were better in R‐PDAC patients (R0 rates, unmatched: 100% vs 87.7%, P=.044; matched: 100% vs 86.7%, P=.045; OS, unmatched: P=.008, matched: P=.021), although there were no significant differences in BR‐PDAC patients. Mesenteric approach might reduce blood loss by early ligation of the vessels to the pancreatic head. Furthermore, it might increase R0 rate, leading to improvement of survival for R‐PDAC patients. However, R0 and survival rates could not be improved only by the mesenteric approach for BR‐PDAC patients. Therefore, effective multidisciplinary treatment is essential to improve survival in BR‐PDAC patients.