Background: Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. Objectives: We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. Design: We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2–carboplatin between 2009 and 2021 in an expert center. Methods: We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. Results: In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2–carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0–6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4–3.0). At multivariable analysis, no extrahepatic metastases ( p = 0.083), no ascites or opioid-requiring pain ( p = 0.023), <2 prior treatment lines ( p < 0.001), full dose of carboplatin ( p = 0.004), and treatment initiation >18 months after initial diagnosis ( p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48–4.92) and was influenced by the presence of extrahepatic metastases ( p = 0.058), opioid-requiring pain or ascites ( p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3–4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Conclusion: Although the efficacy of LV5FU2–carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients.