In this work, a hyperelastic model accounting for cross-linking and microstructural damage is proposed for corneal stroma, where the strengthening mechanisms of the matrix materials, collagen fibers and cross-links, as well as the softening behaviors induced by the damage of collagen fibers and cross-links are systematically addressed. In order to quantitatively characterize the stiffening behavior related to riboflavin/ultraviolet A (UVA)-induced collagen cross-linking, a novel microstructure-based model is proposed that the strain energy function is specified as a function of the density and orientation of cross-links. When addressing the stress softening behavior with respect to the damage of fibers and cross-links, two individual damage variables in an exponential form are considered in the strain energy function as inspired by the pseudo-elastic model. In order to verify the accuracy and rationality of the developed model, uniaxial tensile results of corneal lenticule strips until materials failure are compared between the experimental data and theoretical results at different UVA irradiation doses, and a good agreement is achieved for both the calibrated and predicted results. The unveiled stiffening and damage mechanisms could help assess the clinically relevant issues for corneal stroma, especially from a biomechanical point of view.