The drastic change in the microstructure of nuclear fuels was linked to several degradation mechanisms affecting their performance and integrity during normal operation, transients, and accidents. It is therefore crucial to understand the irradiation-induced co-evolution of microstructure and thermo-mechanical properties of nuclear fuels. In this talk, I will discuss how we can employ a multi-physics modeling approach at the mesoscale to achieve that goal. Particularly, I will elaborate on the best practices of utilizing spatially resolved rate-theory, phase-field, and finite-element modeling methods to simulate radiation damage and effects in selected nuclear fuels. Specific examples will include modeling the mechanical properties and fracture of UO2 and TRISO particles and thermal properties of U-Zr, UO2-BeO, and UO2-Mo fuels. Moreover, the utilization of Machine Learning techniques to derive reduced order models will also be presented in this talk.