Background: African trypanosomiasis, a disease caused by Trypanosoma brucei, remains a significant health challenge in sub-Saharan Africa, particularly in rural communities with limited healthcare access. Despite control efforts, the disease persists due to the parasite's complex immune evasion mechanisms, including antigenic variation and destruction of the host's humoral immune response. Current treatments face limitations, and the development of an effective vaccine is stalled by the parasite's genetic diversity and insufficient research funding. Objective: This review aimed to compile recent advancements in vaccine development against African trypanosomiasis, evaluate potential vaccine candidates, and identify challenges and future directions for developing an effective vaccine. Method: We adopted the PRISMA protocol to guide our systematic literature on Medline/PubMed and Google Scholar databases, focusing on studies published between 2005 and April 2025. Results: The findings revealed several encouraging approaches to vaccine development against African trypanosomiasis. DNA vaccines targeting specific parasite proteins have demonstrated partial protection in animal studies, stimulating immune responses that delay disease progression. The T. brucei membrane surface protein B (Tbmsp-b) gene was cloned into a pVAX-1 plasmid and administered into a BALB/c mice model, conferring partial protection. Similarly, DNA plasmid encoding an invariant surface glycoprotein (ISG) of T. brucei provided partial protection against T. brucei in the BALB/c mice model. Plasmid DNA containing the 5′-terminal region of the T. brucei brucei trans-sialidase (nTSA) gene also provided partial protection in BALB/c mice. Innovative computer-designed vaccines, which combine multiple T. brucei epitopes, showed particular promise against the parasite's variability in terms of antigenicity. Finally, another promising approach involves the application of virus-like particles (VLPs) as vaccine a