Objective: To explore the value of F-18-fluorodeoxyglucose positron emission tomography-computed tomography (F-18-FDG PET/CT) metabolic parameters before and after neoadjuvant chemotherapy in predicting histopathological response and prognosis of locally advanced gastric cancer. Materials and Methods: A total of 56 patients with locally advanced gastric cancer underwent F-18-FDG PET/CT before and after neoadjuvant chemotherapy. The maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the lesions were measured before and after neoadjuvant chemotherapy. The percentage changes in the maximum standardized uptake value (Delta SUVmax%), mean standardized uptake value (Delta SUVmean%), metabolic tumor volume (Delta MTV%), and total lesion glycolysis (Delta TLG%), which were derived from F-18-FDG PET/CT, were calculated, and the cutoff values were determined by receiver operating characteristic curve analysis. Differences in progression-free survival (PFS) and overall survival (OS) between groups dichotomized by these cutoffs were analyzed using the Kaplan-Meier method and Cox proportional hazards regression model. Results: The patients were divided into histopathological responders and nonresponders according to the following cutoff values: 58.8% SUVmax reduction, 45.8% SUVmean reduction, 36.9% MTV reduction, and 57.8% TLG reduction. The differences in PFS and OS between groups dichotomized by these cutoffs were significant (all p < 0.01). Multivariate analysis suggested that a Delta TLG% > 57.8% was an independent postoperative risk factor for PFS (hazard ratio [HR] 0.348, 95% confidence interval [CI] 0.131-0.926, p = 0.035) and OS (HR 0.107, 95% CI 0.023-0.498, p = 0.004). Conclusions: The metabolic parameters before and after neoadjuvant chemotherapy of F-18-FDG PET/CT accurately reflected the chemotherapy effect, and Delta TLG% was the only independent postoperative predictive factor of PFS and OS for locally advanced gastric cancer.