In this study, we evaluated the predictive and prognostic role of HER2 protein/gene expression levels in combination with clinicopathologic features in patients who received neoadjuvant trastuzumab-based chemotherapy. The tumor pathologic complete response (pCR) rate was 40.9%, and the mortality rate was lower than in subjects with a lower response. A better pCR rate correlated with a higher percentage of infiltrating immune cells and right-sided tumors, which reduced distant metastasis and improved survival, but without differences in incidence. HER2 IHC score and laterality emerge as strong predictors of tumor pCR after NACT from machine learning analysis. HER2 IHC3+ and G3 are unfavorable prognostic factors for HER2+ BC patients and could be considered in the application of neoadjuvant therapy. The immune microenvironment and low lymph node involvement play a crucial role in clinical outcomes. The combination of all predictors offer new options for predicting the efficacy of neoadjuvant chemotherapy during clinical decision making.