The Monkeypox virus (MPXV), which causes Monkeypox (Mpox) is an invasive ailment with global implications. MPXV, categorized within the Orthopoxvirus genus, exhibits diverse clades with varying fatality rates. Initially discovered in monkeys and later in humans, the disease predominantly affects regions across West and Central Africa. Clinical manifestations encompass a spectrum from mild flu-like symptoms to severe eruptions. This article aims to give the scientific community a comprehensive overview of Mpox Pathophysiology and delve into the intricate landscape of host immune responses against MPXV infection. It offers crucial insights into the virus's Pathophysiology, spanning its entry, replication, dissemination, and elicited host responses. The immune reaction to Mpox involves innate immunity, B-cell immunity, and T-cell immunity. Moreover, this review underscores the immunological response and resistance mechanisms against MPXV. It also highlights imperative research areas warranting prioritization to devise more efficacious treatments for controlling viral propagation within healthcare systems. In addition, it gives us a look into possible futures that could help the progress of immunotherapies and cutting-edge biotechnological solutions for protecting against MPXV.