Background Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal‐IRI+5‐FU/LV by analyzing a population‐based dataset. Methods We reviewed 667 consecutive mPDAC patients treated with nal‐IRI+5‐FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty‐six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre‐treatment carbohydrate antigen 19‐9 level, lines of prior chemotherapy treatment, and time from first‐line treatment to nal‐IRI+5‐FU/LV therapy. Results The median overall survival and time‐to‐treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups. Conclusions Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal‐IRI+5‐FU/LV treatment in mPDAC patients. HighlightChiu and colleagues conducted a retrospective analysis of a population‐based dataset in Taiwan to investigate the survival outcomes and safety profiles of conventional irinotecan treatment in patients with metastatic pancreatic cancer receiving liposomal irinotecan plus 5‐fluorouracil and leucovorin. Propensity score matching was used to adjust potential confounding variables.