Pancreatic cancer has a high malignancy degree, with an overall 5-year survival rate of only about 11%. Although curative surgery may cure pancreatic cancer, only about 15% of pancreatic cancers are resectable at the time of initial diagnosis. Neoadjuvant therapy provides an opportunity of R₀ resection for some locally advanced pancreatic cancers (LAPC) that are initially unresectable. Neoadjuvant therapy for LAPC is a new treatment modality based on the current treatment status, which is gradually being accepted by clinical surgeons. The emergence of neoadjuvant treatment regimens has led to 20% to 61% of LAPC cases being converted to resectable cases after neoadjuvant therapy. Oxaliplatin, irinotecan, fluorouracil, and calcium folinate (FOLFIRINOX) and gemcitabine combined with albumin-bound paclitaxel (AG) significantly increase the surgical resection rate of LAPC and are the preferred first-line neoadjuvant treatment regimen for LAPC. There are still significant differences in the choice of treatment plan, duration, evaluation indicators, and surgical timing for LAPC neoadjuvant therapy among medical centers. For some LAPC patients who do not meet surgical indications due to inadequate tumor reduction after preoperative systemic chemotherapy, combined chemoradiotherapy can be used as initial treatment. For LAPC patients who cannot tolerate systemic chemotherapy, stereotactic body radiation therapy (SBRT) can be used to control local tumor progression. The treatment targets for pancreatic cancer include KRAS, EGFR, PARP, and NTRK, among others. The NCCN guidelines recommend genetic testing for all LAPC patients to guide the best drug treatment plan and participate in clinical trials of new drugs. Pancreatic cancer immunotherapy mainly includes immune checkpoint inhibitors, adoptive T-cell therapy, and tumor vaccines. Pembrolizumab is the only second-line treatment approved by the US Food and Drug Administration for microsatellite-instability-high or mismatch-repair-deficient solid tumors, including pancreatic cancer. Currently, adoptive T-cell therapy is limited to metastatic pancreatic cancer. The GVAX tumor vaccine is in the clinical trial stage. There is a synergistic effect between immunotherapy and certain targeted drugs, such as antiangiogenic factors and tyrosine kinase inhibitors. Future immunotherapy should aim to combine multiple new immunotherapy strategies, as well as cytotoxic drugs and/or local ablation therapy, to target tumor-induced immune escape mechanisms. The main challenge of combination therapy will be drug selection, administration sequence, and dosage. It is worth actively recommending the approach of selecting specific LAPC patients for neoadjuvant therapy followed by surgery. It is difficult to evaluate the resectability of tumors after neoadjuvant therapy through imaging evaluation, as CT cannot accurately distinguish between tumor tissue and fibrous tissue. 18F-FDG PET is more accurate than CT in determining the R₀ resectability of pancreatic cancer, but high-quality evidence is still needed to further confirm this. Other evaluations of the effectiveness of neoadjuvant therapy include a decrease in serum tumor marker levels and improvement in clinical symptoms. Liquid biopsy techniques, including the detection of circulating tumor cells, circulating tumor DNA, and exosomes, have shown potential applications in the determination of micrometastases and the evaluation of neoadjuvant therapy efficacy. Long-term survival rates of LAPC patients who underwent surgical resection after neoadjuvant therapy have been improved. Innovative techniques such as adventitial dissection and autologous small bowel transplantation can assist in surgical resection after neoadjuvant therapy. Here, the authors provide a review and discussion of the current status and progress of neoadjuvant therapy for LAPC.