Background: Localized pancreatic adenocarcinoma (PDAC) includes resectable, borderline resectable, and locally advanced cancers. In potentially resectable pancreatic cancer, the role of neoadjuvant therapy is evolving and guidelines from expert groups are conflicting. Although limited, randomized trials have shown that neoadjuvant chemotherapy (NCT) can provide survival benefits in patients with localized PDAC. Studies have compared FOLFIRINOX (FFN) with Gemcitabine plus nab-Paclitaxel (G-nP) as first-line NCT for PDAC, but no consensus has been established. As a result, we performed an updated meta-analysis to assess the difference in overall survival between two chemotherapy regimens. Methods: PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception to December 2021 to identify studies comparing FFN with G-nP in the neoadjuvant settings for localized PDAC. The primary outcome was the overall survival of patients and secondary endpoints were RECIST partial or complete response, resection rate and R0 resection. The effectiveness of FOLFIRINOX and G-nP in terms of overall survival in patients with localized PDAC was compared using hazard ratios (HR) and 95% confidence intervals (CI). In addition, the heterogeneity of the studies was evaluated using Cochrane's Q test of heterogeneity and the I² statistic. Pooled analysis of HR was performed with Stata 17 METAN using random effect model and P of 0.05 was considered statistically significant. Results: We identified 10 studies that met our inclusion criteria. All studies were retrospective and 5 of them were carried out in the United States. The total numbers of patients preoperatively treated with FOLFIRINOX versus G-nP were 988 and 719, respectively. In this meta-analysis compared to G-nP, neoadjuvant FFN was associated with significant prolonged overall survival (HR = 0.72, 95% CI: 0.63–0.82, P < 0.001). FFN group had a significantly higher RECIST partial and complete response rate than the G-nP group, with an OR of 1.65 (95 % CI 1.02-2.68, p = 0.04). For resection rate and R0 resection, FFN group had ORs of 1.65 (95% CI 0.94-2.90, p = 0.08) and 1.91 (95% CI 0.95-3.81, P = 0.07) respectively, both outcomes were statistically insignificant. Conclusions: Results of our meta-analysis show that for localized pancreatic cancer, neoadjuvant treatment with FFN was associated with better survival than G-nP. One limitation to our current study was that all included studies were designed retrospectively. Further randomized clinical trials are needed to explore the ideal neoadjuvant chemotherapy for PDAC.