Background: The 2019 NCCN guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for locally advanced and borderline resectable pancreatic ductal adenocarcinoma (BR/LA PDAC). Neoadjuvant FOLFIRINOX and G-nP have yet to be directly compared in a prospective, randomized trial with BR/LA PDAC patients. The purpose of our study was to incorporate treatment outcomes, toxicity profiles, costs, and quality-of-life measures to further inform clinical decision-making. Methods: We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over twelve years. Adjuvant gemcitabine (GEM) was used as a comparator. The inputs for the model were estimated using clinical trial data and published literature. We used single-institution retrospective studies to estimate our survival data in the absence of a prospective trial. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100,000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care (USD), QALYs, patient resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). Results: FOLFIRINOX was the cost-effective strategy, totaling incremental QALYs of 0.21 at a cost of $52,845.96 per QALY when compared to G-nP. G-nP was also on the efficiency frontier with an ICER of $46,430.73 compared to GEM. More patients received resection with FOLFIRINOX (82.15% vs. 72.40%), but had higher TRAE costs than G-nP ($12,051.26 vs. $4,666.97). A one-way sensitivity analysis found that the FOLFIRINOX ICER exceeds the WTP threshold when TRAE costs are higher and resection rates are lower. Conclusions: Our modeling analysis finds FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings.