Lorazepam is frequently used in pancreatic cancer patients receiving chemotherapy for its antiemetic properties and to mitigate psychological distress. However, N-unsubstituted benzodiazepines like lorazepam may adversely impact pancreatic cancer progression by stimulating fibrosis and inflammatory signaling. This study aimed to retrospectively compare the survival rates of pancreatic cancer patients exposed to lorazepam with those who were not exposed to real-world clinical practice. Data were retrospectively reviewed from patients aged ≥ 18 years with pathologically confirmed pancreatic cancer who received palliative chemotherapy at Seoul National University Hospital between January 2011 and January 2023. Patients were dichotomized based on lorazepam administration: those who received ≥ 15 mg (equivalent to ≥ 1 tablet daily for 30 days) were classified as the high-dose group, and those who received < 15 mg were classified as the low-dose group. The relationship between lorazepam exposure and progression-free survival (PFS), as well as overall survival (OS), was analyzed. Among pancreatic cancer patients undergoing palliative chemotherapy, PFS was worse in the high-dose lorazepam group compared to the low-dose group [median, 6 months (5–7) vs. 8 months (7–9), p = 0.025]. However, there was no difference in OS between the two groups [median, 11 months (10–12) vs. 12 months (11–13), p = 0.465]. Higher cumulative lorazepam exposure was associated with shorter progression-free survival in Asian patients with pancreatic cancer treated with palliative chemotherapy.