Leishmaniasis is an infectious parasitic disease located in tropical and subtropical regions of the world, including many African countries. Infection is caused by the bite of sand fly leading to cutaneous leishmaniasis (CL) that may develop into mucosal leishmaniasis (ML). Visceral leishmaniasis (VL) is a serious form of disease affecting the internal organs with a high mortality rate. There are several anti-parasitic medications used to treat leishmaniasis as amphotericin, miltefosine, antimonials, and paromomycin. Unfortunately, the long-term use of these drugs reduces their effectiveness and leads to multiple side effects. Thus, natural products may offer a convenient alternative or complementary treatment for leishmaniasis. This book chapter piles up the biological studies (2018–2024) describing the potential role of African medicinal plants and their secondary metabolites in the treatment of this disease, focusing on their efficacy and highlighting the mechanism of action. Results revealed that different 52 plant extracts showed variable in vitro antileishmanial activity while eight plant extracts treated cutaneous and visceral leishmaniasis in experimental animals significantly and could represent a starting point for clinical trials. Regarding pure isolated compounds, terpenes exhibited high antileishmanial activity compared to standard drugs. Additionally, most endophytic compounds exhibited leishmanicidal activity with IC50 values less than 50 μM.