Serious games in health education require structured design approaches that strike a balance between pedagogical effectiveness and engaging gameplay. This chapter examines the evolution of design methodologies developed specifically for educational game development, analyzing how different models address the unique challenges faced by multidisciplinary health education teams. Through comparative analysis, we explore three established frameworks: The Design-Play-Experience (DPE) model, which provides systematic organization of game elements; the Activity Theory-Based Model of Serious Games (ATMSG), which grounds design decisions in educational theory; and the Learning Mechanics-Game Mechanics (LM-GM) framework, which ensures alignment between instructional strategies and interactive features. Building upon these foundations, the chapter presents a detailed examination of the Art of Serious Game Design (ASGD) framework—a collaborative methodology specifically developed for education contexts. ASGD addresses the limitations of existing models by providing structured yet flexible tools for interdisciplinary teams, including ideation cards, visual canvases, and iterative design processes. Through practical examples and framework comparisons, this chapter demonstrates how structured design approaches can bridge the gap between educational theory and game development practice, enabling healthcare educators, instructional designers, and developers to create compelling learning experiences that maintain clinical accuracy while fostering engagement.