Chemically treated, biologically derived tissues are used extensively in cardiac valve bioprostheses. Unfortunately, while extensive research has focused on chemical treatment technologies to reduce negative in-vivo effects such as mineralization and to enhance overall biocompatibility, little work has been done on understanding the effects of fatigue on tissue mechanical properties. In the current work, a structure-based damage mechanics model for the evolution of mechanical properties with cyclic loading of chemically treated soft tissues is presented. The model is used to clarify and relate the impact of different structural changes, such as collagen fiber debonding and collagen fiber weakening, to changes in macro-level tissue mechanical properties. The fatigue damage model will ultimately serve as a guide for the development of key experiments for fatigue damage assessment of novel chemical treatment technologies. This will aid in the rational development, as opposed to the current ad-hoc approach, of novel chemically modified collagenous biomaterials for more durable cardiac valve bioprostheses.