Mpox, caused by the Monkeypox virus (MPXV), has emerged as a significant global public health concern, particularly affecting vulnerable populations. The recent outbreak in the Democratic Republic of the Congo (DRC) is the largest recorded, driven by the highly virulent clade 1 strain. Transmission has shifted from animal contact to primarily sexual contact among Key Populations (KPs) such as Sex Workers (SW) and Men who have Sex with Men (MSM). In Zanzibar, where HIV prevalence is significantly higher among Key Populations, People Living with Human Immunodeficiency Virus (PLHIV) are at increased risk of Mpox infection due to socioeconomic challenges and immunosuppression. Despite no reported cases in Zanzibar, the spread of Mpox in non-endemic areas highlights the need for proactive measures. Leveraging Zanzibar’s strengthened public health infrastructure, key strategies include tailored awareness campaigns, improved vaccine access through existing COVID-19 vaccination models, healthcare infrastructure enhancement, and mental health support. These targeted actions aim to protect Zanzibar’s most vulnerable populations and bolster preparedness against Mpox, emphasizing the importance of resource-appropriate interventions to mitigate potential outbreaks.© 2024. The Author(s).