Morphine is a globally prevalent substance of misuse, renowned for its immunosuppressive effects mediated through opioid receptors expressed on immune cells. Macrophages are crucial antigen-presenting cells that fulfill diverse roles, such as antigen presentation, phagocytosis, wound healing, and disease protection. They are typically classified based on their activation states: M1 (proinflammatory), M2 (anti-inflammatory), and M0 (resting). Morphine significantly modulates immune responses and neuroinflammation, further complicating the landscape of opioid dependency and disease susceptibility. The association of macrophages under the influence of morphine needs to be understood under various diseased conditions. Several studies have been focused on investigating the impact of morphine on macrophage function and its implications in infectious diseases and brain-associated diseases. To light this subject, we have discussed recent advancements in understanding the influences between morphine, macrophage function, polarization, infection, brain tumors, and drug dependency. This article explores the complex relationship between morphine, macrophages, and related pathologies. Consequently, discussing deeper insights into these dynamics could guide effective treatments for substance abuse disorders.