HER2-positive breast cancer accounts for 15% to 20% of all breast cancers and is a critical focus in treatment. Common HER2-targeted drugs like trastuzumab and pertuzumab improve patient prognosis, but resistance remains a challenge. Aberrant activation of the PI3K/AKT pathway is prevalent in HER2-positive breast cancer, with p-AKT linked to poor outcomes. The PI3K/AKT pathway is a major contributor to drug resistance. This review summarizes molecular alterations in HER2-positive breast cancer, explores the relationship between HER2 overexpression and PI3K/AKT pathway changes, and discusses mechanisms of resistance to HER2-AKT pathway-targeted drugs. It aims to provide insights for future therapeutic strategies. The HER2 protein is a transmembrane tyrosine kinase receptor involved in cell proliferation and survival. HER2 overexpression is associated with aggressive tumor behavior and poor prognosis. HER2 signaling involves interactions with other HER family members, leading to activation of pathways like PI3K/AKT, MAPK, and PLCγ. These pathways regulate cell proliferation, survival, and metastasis. The HER2-AKT pathway is crucial for tumor growth and resistance to therapy. The PI3K/AKT pathway is a key signaling pathway in breast cancer, with AKT playing a central role. Activation of AKT involves phosphorylation and is regulated by various mechanisms, including lipid and protein phosphatases. Dysregulation of the PI3K/AKT pathway is common in breast cancer, often due to mutations in PIK3CA or loss of PTEN. These alterations contribute to resistance to HER2-targeted therapies. Common genetic alterations in HER2-positive breast cancer include HER2 amplification, mutations, and other RTK changes. HER2 mutations, such as V777L, L755S, and D769Y, are associated with resistance to HER2-targeted drugs. PIK3CA mutations are also prevalent and contribute to PI3K/AKT pathway activation. These mutations enhance tumor growth and resistance to therapy. The HER2-AKT pathway plays a significant role in breast cancer progression and resistance to treatment. HER2 overexpression and PI3K/AKT pathway alterations are linked to increased tumor aggressiveness and poor prognosis. Targeting the HER2-AKT pathway with drugs like trastuzumab, pertuzumab, and PI3K/AKT inhibitors is a promising approach. However, resistance mechanisms, including HER2 splice variants and other pathway alterations, complicate treatment. Drugs targeting the HER2-AKT pathway include HER2-targeted monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and PI3K/AKT inhibitors. These drugs aim to inhibit HER2 signaling and downstream pathways, improving treatment outcomes. However, resistance mechanisms, such as HER2 mutations and pathway dysregulation, remain a challenge. Understanding these mechanisms isHER2-positive breast cancer accounts for 15% to 20% of all breast cancers and is a critical focus in treatment. Common HER2-targeted drugs like trastuzumab and pertuzumab improve patient prognosis, but resistance remains a challenge. Aberrant activation of the PI3K/AKT pathway is prevalent in HER2-positive breast cancer, with p-AKT linked to poor outcomes. The PI3K/AKT pathway is a major contributor to drug resistance. This review summarizes molecular alterations in HER2-positive breast cancer, explores the relationship between HER2 overexpression and PI3K/AKT pathway changes, and discusses mechanisms of resistance to HER2-AKT pathway-targeted drugs. It aims to provide insights for future therapeutic strategies. The HER2 protein is a transmembrane tyrosine kinase receptor involved in cell proliferation and survival. HER2 overexpression is associated with aggressive tumor behavior and poor prognosis. HER2 signaling involves interactions with other HER family members, leading to activation of pathways like PI3K/AKT, MAPK, and PLCγ. These pathways regulate cell proliferation, survival, and metastasis. The HER2-AKT pathway is crucial for tumor growth and resistance to therapy. The PI3K/AKT pathway is a key signaling pathway in breast cancer, with AKT playing a central role. Activation of AKT involves phosphorylation and is regulated by various mechanisms, including lipid and protein phosphatases. Dysregulation of the PI3K/AKT pathway is common in breast cancer, often due to mutations in PIK3CA or loss of PTEN. These alterations contribute to resistance to HER2-targeted therapies. Common genetic alterations in HER2-positive breast cancer include HER2 amplification, mutations, and other RTK changes. HER2 mutations, such as V777L, L755S, and D769Y, are associated with resistance to HER2-targeted drugs. PIK3CA mutations are also prevalent and contribute to PI3K/AKT pathway activation. These mutations enhance tumor growth and resistance to therapy. The HER2-AKT pathway plays a significant role in breast cancer progression and resistance to treatment. HER2 overexpression and PI3K/AKT pathway alterations are linked to increased tumor aggressiveness and poor prognosis. Targeting the HER2-AKT pathway with drugs like trastuzumab, pertuzumab, and PI3K/AKT inhibitors is a promising approach. However, resistance mechanisms, including HER2 splice variants and other pathway alterations, complicate treatment. Drugs targeting the HER2-AKT pathway include HER2-targeted monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and PI3K/AKT inhibitors. These drugs aim to inhibit HER2 signaling and downstream pathways, improving treatment outcomes. However, resistance mechanisms, such as HER2 mutations and pathway dysregulation, remain a challenge. Understanding these mechanisms is