Background: The role of neoadjuvant chemotherapy (NAC) for resectable pancreatic cancer (RPC) remains controversial. We sought to compare the outcomes of NAC with upfront surgery (UFS). Methods: The study retrospectively enrolled patients with RPC who had UFS or received neoadjuvant FOLFIRINOX (FFX) or gemcitabine plus albumin-bound paclitaxel (GA). Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher’s exact test for categorical variables. The overall survival (OS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method with Wilcoxon test for the difference between groups. The effects of NAC vs. UFS on OS and RFS were further estimated using Cox regression controlling the effects of age and CA 19-9. Results: Between 2011 and 2019, 131 patients with RPC underwent UFS followed by adjuvant chemotherapy (gemcitabine, n = 65; gemcitabine/capecitabine, n = 18; FFX, n = 9). Up to 32 patients (24.4%) could not receive adjuvant chemotherapy due to surgical complications or poor recovery. Total 50 patients with RPC received NAC (FFX, n = 32; GA, n = 18). Median of 5.5 cycles of FFX or 3 cycles of GA were given prior to surgery. Resection rate was 72% (FFX 62.5%; GA 88.9%). The rest (28%) were no longer surgical candidates due to disease progression rather than toxicities from NAC. On surgical pathological review, complete resection (R0) was achieved in 83.3% of resected cases after NAC (FFX 90%; GA 75%) and 79.4% with UFS. The tumor size distribution was: pT1 11.1%, pT2 41.7%, pT3 44.4% with NAC; pT1 5.4%, pT2 18.3%, pT3 76.3% with UFS. The nodal status distribution was: pN0 27.8%, pN1 55.5%, pN2 16.7% with NAC; pN0 23.7%, pN1 71.0%, pN2 5.3% with UFS. Median pre-treatment CA 19-9 was 321.95 unit/mL in the NAC group and 79.99 unit/mL in the UFS group (p = 0.009). Median age was 70.5 in the NAC group and 72 in the UFS group (p = 0.374). There was no significant difference in the performance status between the two groups. In Kaplan-Meier analysis, there was a significant difference of OS between UFS and NAC with median OS of 648 days under UFS versus 884 days under NAC (p = 0.029); the median of RFS was 390 days under UFS versus 392 days under NAC (p = 0.953). The hazard ratio (NAC vs UFS) adjusted for CA19-9 and age was 0.7 (p = 0.176) for OS and 0.98 (p = 0.918) for RFS. Conclusions: We observed a signal of tumor downstaging, higher R0 rate, and improved OS with NAC compared with UFS. Further prospective trials are needed to validate these results.