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The number of new COVID-19 cases continues to rise rapidly in many countries despite vaccination. The best way to counter the spread of COVID-19 is self-protection. This study documents the development of a web-based serious game (WSG-COVID-19.SP) to promote effective learning strategies for self-protection against COVID-19 and to test the game’s content validity and usability. WSG-COVID-19.SP was developed using situated learning theory and diagnostic feedback mechanism. The game includes six situation storylines with 17 learning objectives. It uses a problem-solving approach to foster practices such as wearing masks, washing hands, and social distancing. Portfolio analysis was used to diagnose learning problems and report on the learning process. An overall summary index—the scale-level content validity index (S-CVI)—was used to evaluate content validity. Usability was tested through a website survey from 71 students from one university to gauge their technological acceptance and the game’s capability to promote future self-protection behaviors. The S-CVI was 0.81. Usability and acceptability were neither related to the users’ college major (whether it is information technology-related) nor to gender. Among the respondents, 84.5% agreed to continue with the self-protection practice as they were motivated by the real-time diagnostic function. The WSG-COVID-19.SP game system has adequate content validity and a high user satisfaction rating.