Purpose Microcalcification (MC) is a valuable diagnostic indicator to detect invasive breast cancer (IBC). This study aimed to determine the clinicopathological features of IBC with MC and detect biomarkers related to the potential mechanism of the MC formation in IBC. Methods Data from 364 patients with IBC were collected for the clinical characteristic analysis. The analysis of clinical data helped us to establish a predictive model of axillary node metastasis (ANM) before surgery. In addition, 49 tissue samples of IBC patients were collected to test the protein levels of osteocalcin (OCN) and hypoxia‐inducible factor‐1α (HIF‐1α) by immunohistochemistry. Results Significant differences were observed in tumor size, age, ANM, HER2+, TNM stage, and mutant P53 between samples from IBC patients with MC and samples from IBC patients without MC. Younger age, a larger tumor size, a higher number of childbirths, and MC were independent predictors for ANM in IBC. HIF‐1α protein level was higher in tumor tissue than in normal tissue. High protein levels of OCN and HIF‐1α are related to the complication of MC in IBC. Of the patients that exhibited high HIF‐1α protein levels, the percentage of high OCN protein levels was larger in patients with ANM. Conclusion Based on this study, we concluded that patients with MC had a comparatively poor prognosis. MC was an independent predictive factor associated with the risk of ANM. High protein levels of OCN and HIF‐1α were associated with MC and ANM, which were also related to poor prognosis. OCN and HIF‐1α had a positive correlation in IBC. MCs were an independent predictor for ANM risk. Our results provide a possibility for the prediction of ANM and prognosis in IBC and may offer novel therapeutic choices targeting calcification‐involved proteins.