The implementation of digital games in biology education has steadily increased over the past decade. The utilization of simulation-based learning tools, such as digital games, is anticipated to be further enhanced due to the increasing shift toward virtual learning. This review aims to explore the existing scientific evidence and analyze the effectiveness of incorporating digital games as a learning tool in biology education. The research methodology was a systematic literature review of existing digital game-based learning (DGBL) in biology education. The term “digital game-based learning and education” was utilized in the search interface of the Scopus database, identifying 1,241 articles. However, only 56 articles adhered to the stipulated criteria for subsequent analysis. Preferred reporting items for systematic reviews and meta-analyses framework was employed for the process of inclusion and exclusion. A discernible trend of escalating publications has been observed over the past decade. The review findings indicate that DGBL has expanded widely, encompassing all levels of education, from elementary to higher education, and has even been applied in professional education. Researchers primarily utilize quantitative research methods, although qualitative methods are employed. This research found that the complexity of DGBL research requires interdisciplinary collaboration involving science, biomedical, education, and technology experts. In terms of content, DGBL has been used to teach students about basic biology and practical applications of biology, such as biomedical science. Genetics, environment, and healthcare emerged as the most frequently addressed subjects taught using DGBL. Trends in DGBL technology usage include various platforms like computer-based, internet-based, and mobile-based, with elements of gaming and social interaction that align with the demands of 21<sup>st</sup> century skills. DGBL integrates with several constructivist learning approaches like experiential learning, problem-based, inquiry-based, and inquiry-lab. Research showed that DGBL encourages development of 21<sup>st</sup> century skills in simulated settings and real-life situations.