Background: Reminding health care workers, especially senior students, of the critical role they play in preventing COVID-19 transmission is more important than ever, therefore it is vital to reinforce graduate students' intrinsic motivation to implement infection prevention and control guidelines. Serious games are an interesting intervention that could improve adherence to COVID-19 safe behaviors to lower the high prevalence of nosocomial infections. These games, as a type of technology-enhanced simulation, can increase student satisfaction and engagement while still conveying vital ideas. For this reason, this study aimed to develop a serious game and evaluate its effectiveness to prevent the spread of infection and develop safe behaviors during the COVID-19 pandemic. Methods: In total, 62 nursing students completed a socio-demographic questionnaire, COVID-19 information form, and game usability form, with the students’ responses analyzed pre-test and post-test. Results: Serious game implementation significantly increased senior students’ knowledge of infection and safe behaviors concerning COVID-19. The students also considered the practice of serious games an effective teaching strategy. Favorite aspects of the serious game according to students' statements; It was reported as reflecting the real hospital environment, including the nursing care process and roles, being informative, being compatible by phone, and each stage of the game tested a new knowledge. Conclusion: Employing serious games for nursing skills development is an appropriate teaching method for infection prevention and promotion of safe behaviors among senior nursing students during the COVID-19 pandemic. This game can be obtained free of charge for research and educational purposes.