Monkeypox virus (MPXV) is the causative agent of the monkeypox (Mpox) disease, belongs to the Orthopoxvirus genus of the Poxviridae family. Due to the recent re-emergence of Mpox in 2024, this is the second time when the World Health Organization (WHO) declared Mpox as a Public Health Emergency of International Concern (PHEIC). This review intends to offer an in-depth analysis of Mpox, including its key characteristics, epidemiological, mutation, pathophysiology, transmission, and therapeutics. The infection of MPXV is a lethal threat to children, pregnant women, and immunocompromised individuals. However, we can prevent the infection by proper precautions including hygiene practices and minimizing exposure to infected individuals or animals. Multivalent mRNA vaccines, antibody-based immunotherapy, and combination drug therapies have all shown significant effectiveness in treating Mpox infection. In addition to addressing antivirals and drug resistance, the review also explores potential targets for vaccine and drug development, as well as the use of animal models for studying MPXV. Because of multiple mutational events, Mpox began exhibiting drug resistance. Overall, this review will contribute significantly to advancing the development of new vaccines and drug options for combating emerging Mpox.