This work presents a physics- and chemistry-informed constitutive modeling framework to predict the effects of thermo-oxidative aging on the mechanical response and fracture behavior of semi-crystalline polyimide films. The framework couples viscoelastic constitutive behavior with a phase-field fracture formulation to capture aging-induced degradation under prolonged thermal and oxidative exposure. Although polyimides are widely used in high-temperature aerospace and electronic applications due to their exceptional thermal stability and mechanical performance, long-term exposure to extreme environments leads to progressive degradation that can compromise structural reliability. Predicting aging-driven failure mechanisms is therefore essential for assessing their long-term performance. Aging effects are incorporated through degradation functions that scale the bulk modulus, shear modulus, and fracture energy as functions of evolving physico-chemical state variables. These degradation laws are formulated using experimentally measurable metrics, including changes in crystallinity and chemical bond structure, enabling the model to capture key aging phenomena such as stiffness reduction, embrittlement, and loss of fracture resistance. The coupled framework reproduces the progressive deterioration in mechanical response and fracture behavior observed in aged polyimide films. The model is developed and validated using experimental data from PMDA-ODA polyimide films aged in air at 300 °C for up to five weeks. Mechanical and fracture behavior are characterized through uniaxial tensile and single-edge notch tension tests, while Raman spectroscopy and X-ray diffraction are employed to quantify molecular- and microstructural-level changes. These experimental measurements inform both the calibration and validation of the constitutive framework. The proposed approach provides a predictive tool for assessing the long-term mechanical integrity and failure of polyimide-based components operating under extreme thermo-oxidative environments, with direct relevance to aerospace and high-temperature structural applications.