Insulin resistance (IR) is closely associated with the risk of breast cancer. The triglyceride-glucose (TyG) index and the triglyceride-glucose-body mass index (TyG-BMI) are considered surrogate indicators of IR; however, their prognostic value in breast cancer patients has not been discussed. The purpose of this study is not only to explore whether the TyG index and the TyG-BMI can predict the chemotherapy response and long-term prognosis of breast cancer patients receiving neoadjuvant chemotherapy (NACT) but also to investigate the possible mediating mechanism and to analyze the relationship between TyG-related enzyme expression and drug resistance and prognosis.From November 2011 to December 2018, a total of 335 breast cancer patients referred to Harbin Medical University Cancer Hospital who received NACT and surgery were registered in this retrospective study. The TyG index and TyG-BMI before the first chemotherapy were retrospectively calculated. Tissue samples of breast cancer patients were obtained from the Cancer Genome Atlas database, and the associations between the expression levels of the FBP1 and G6PD enzymes and the clinicopathological features and prognosis of breast cancer were analyzed.In receiver operating characteristic analyses, the optimal cutoff values for the TyG and TyG-BMI were determined at 8.01 and 194.91, respectively. Low levels of the TyG and TyG-BMI were not associated with pathological complete response. In multivariate analysis, high TyG was an independent prognostic factor for shorter disease-free survival (DFS; HR = 2.402, P = 0.008) and overall survival (OS; HR = 3.206, P = 0.010). After adjustments for the age group, cT stage group, and cN stage group, the dose-response relationships between TyG, TyG-BMI, and survival outcomes showed a linear correlation by restricted cubic spline analyses. Lg-transformed BMI did not significantly (P > 0.05) mediate the recurrence, metastasis, and deaths associated with TyG. The expressions of two enzymes related to TyG, FBP1 and G6PD, were higher in breast cancer tissues than in the adjacent normal tissues and were associated with the TNM stage. Survival analysis shows that patients with high expressions of FBP1 and G6PD have a shorter OS.This study suggests that the TyG index level before NACT is an independent prognostic factor for DFS and OS and can serve as a promising biomarker to predict the long-term prognosis of breast cancer patients undergoing NACT. Moreover, the TyG index and TyG-BMI show a linear correlation with DFS and OS. The effect of the TyG index on DFS and OS is not significantly mediated by lg-transformed BMI. Besides, FBP1 and G6PD are prognostic indicators for breast cancer patients and may serve as biomarkers for the clinical diagnosis and treatment of breast cancer.