Monkeypox disease is caused by the monkeypox virus (MPXV) infection and is associated with international travel or imported animals. Since May 2022, the number of newly reported cases each week has increased dramatically, leading the WHO to declare this outbreak as a public health emergency of international concern. To evaluate antibody response and disease status after monkeypox vaccination using the smallpox vaccine. The authors followed the PRISMA guidelines to systematically search and collect literature from the following databases: ProQuest, PubMed, EBSCOhost, SAGE, Taylor & Francis, and GARUDA without time restrictions. Titles and abstracts were reviewed for relevance. The inclusion criteria were original articles written in English that investigated the effects of smallpox vaccination on MPXV infection. A total of 973 studies were initially identified through database searching. After removing duplicates and screening titles and abstracts based on the predefined inclusion and exclusion criteria, potentially relevant articles were assessed through full-text review. Following this eligibility assessment, 30 studies were included in the final analysis. These included cohort studies (n=1), case-control studies (n=1), case reports (n=1), and in vivo studies (n=27) published between 2002 and 2022. Two types of smallpox vaccines were used: live attenuated vaccines (n=24) and subunit vaccines made from protein (n=1), virus-like replicon particles (n=1), and DNA virus (n=5). The overall results showed that post-exposure vaccination protected subjects and could induce long-term protection against severe MPXV infection. Subunit vaccines against MPXV could also serve as a safer alternative to live attenuated vaccines. Smallpox vaccination is recommended for high-risk groups susceptible to monkeypox infection. Specific vaccines for monkeypox infection are still being developed. This systematic review found that the overall potential of smallpox vaccines is quite satisfactory in preventing MPXV infection.