Time-varying effects simulation plays a critical role in computer graphics. Fruit diseases are typical time-varying phenomena. Due to the biological complexity, the existing methods fail to represent the biodiversity and biological law of symptoms. To this end, this paper proposes a biology-aware, physically-based framework that respects biological knowledge for realistic simulation of fruit mildew diseases. The simulated symptoms include skin discoloration, fungus growth, and volume shrinkage. Specifically, we take advantage of both the zero-order kinetic model and reaction–diffusion model to represent the complex fruit skin discoloration related to skin biological characteristics. To reproduce 3D mildew growth, we employ the Poisson-disk sampling technique and propose a template model instancing method. One can flexibly change hyphal template models to characterize the fungal biological diversity. To model the fruit’s biological structure, we fill the fruit mesh interior with particles in a biologically-based arrangement. Based on this structure, we propose a turgor pressure and a Lennard-Jones force-based adaptive mass–spring system to simulate the fruit shrinkage in a biological manner. Experiments verified that the proposed framework can effectively simulate mildew diseases, including gray mold, powdery mildew, and downy mildew. Our results are visually compelling and close to the ground truth. Both quantitative and qualitative experiments validated the proposed method.