Cancer continues to be a leading cause of morbidity and mortality globally, which necessitates the development of more effective and less toxic therapies. Quinoxaline derivatives, a class of heterocyclic compounds with versatile chemical structures, have emerged as promising candidates for anticancer drug development. These derivatives exhibit a range of biological activities and have shown significant efficacy against various tumors. However, the therapeutic potential of quinoxaline derivatives, particularly in clinical applications, remains underexplored, highlighting the need for further research to optimize their use as anticancer agents. This systematic review aims to provide an updated analysis of quinoxaline derivatives’ anticancer potential, focusing on their mechanisms of action and therapeutic applications in oncology. Following PRISMA guidelines, a thorough search was conducted in MEDLINE/PubMed and Science Direct for studies from 2020 to 2024. Relevant keywords were used to identify studies on quinoxaline derivatives and their anticancer properties, resulting in the selection of 77 studies based on pharmacological activity and mechanisms. The review included 77 studies exploring various anticancer activities of quinoxaline derivatives. Key findings indicate that these compounds effectively inhibit cancer cell growth through multiple mechanisms, including the inhibition of topoisomerases, kinases, and other critical proteins involved in cancer progression. Additionally, they demonstrate strong antiproliferative and pro-apoptotic effects across several cancer cell lines, highlighting their broad therapeutic potential. Quinoxaline derivatives represent a promising class of compounds in anticancer therapy due to their diverse biological activities and multiple molecular targets. The development of these derivatives as targeted therapies holds the potential for more effective cancer treatments.