Midkine (MDK), a heparin-binding growth factor, is known to be overexpressed in lung cancer (LC) cells. In this study, we investigated the role of MDK in lung cancer brain metastasis (LCBM) and aimed to elucidate the underlying mechanisms involved. Proteomic analysis revealed significant upregulation of MDK in LCBM samples. The expression levels of MDK correlated with the migration and invasion of lung cancer cells. Overexpression or knockdown of MDK correspondingly enhanced or reduced the proliferation, invasion, and migration abilities of lung cancer cells, respectively. Furthermore, our research indicated that MDK plays a pivotal role in regulating the NOTCH2/HES1 and PI3K/AKT signaling pathways. In vivo experiments confirmed that silencing MDK significantly inhibited the formation of brain metastases from lung cancer cells. In lung cancer patients, elevated MDK expression has emerged as a significant risk factor for the development of brain metastasis. This study underscores the crucial role of MDK in facilitating LCBM, presumably by activating the NOTCH2/HES1 and PI3K/AKT pathways. These findings pave the way for exploring MDK as a promising therapeutic target for the prevention or treatment of LCBM.