High mobility group AT-hook 2 (HMGA2) is a member of the non-histone chromosomal high mobility group (HMG) protein family, which participate in embryonic development and other biological processes. HMGA2 overexpression is associated with breast cancer (BC) cell growth, proliferation, metastasis, and drug resistance. Furthermore, HMGA2 expression is positively associated with poor prognosis of patients with BC, and inhibiting HMGA2 signaling can stimulate BC cell progression and metastasis. In this review, we focus on HMGA2 expression changes in BC tissues and multiple BC cell lines. Wnt/β-catenin, STAT3, CNN6, and TRAIL-R2 proteins are upstream mediators of HMGA2 that can induce BC invasion and metastasis. Moreover, microRNAs (miRNAs) can suppress BC cell growth, invasion, and metastasis by inhibiting HMGA2 expression. Furthermore, long noncoding RNAs (LncRNAs) and circular RNAs (CircRNAs) mainly regulate HMGA2 mRNA and protein expression levels by sponging miRNAs, thereby promoting BC development. Additionally, certain small molecule inhibitors can suppress BC drug resistance by reducing HMGA2 expression. Finally, we summarize findings demonstrating that HMGA2 siRNA and HMGA2 siRNA-loaded nanoliposomes can suppress BC progression and metastasis.