Lyophilized organ extracts from livestock such as beef or elk are widely commercially proposed as animal-sourced nutraceuticals. Such preparations contain blends of vitamins and nutrients that may be employed for general or specific dietary supplementation. The first objective of this study was to develop an optimized and function-oriented manufacturing process for stabilized organ-specific extracts of American buffalo (Bison bison). The second objective of the study was to perform functional benchmarking of the obtained stabilized extracts by focusing on antioxidant attributes, which are key properties of nutraceuticals. Methodologically, a two-step lyophilization process, hard-shell capsule formulation, and process quality control elements were adapted from pharmaceutical technology practices. Stabilized extracts (300 mg capsules) were derived from the spleen, heart, liver, kidneys, lungs, and thymus of grass-fed and grass-finished American bison (born and raised in a tempered climate in Geneva, Switzerland). Functional benchmarking of the obtained extracts was performed using orthogonal methods of antioxidant activity determination (TEAC, FRAP, and H2O2 challenge assays). Firstly, the developed biomass transformation process enabled the considered organs to be effectively stabilized while reaching the desired quality attributes. Secondly, functional characterization of the formulated extracts revealed significant and organ-specific antioxidant attributes, wherein liver-derived materials were found to be the most potent. Thirdly, key quality and functional parameters (residual moisture levels and TEAC) were found to be stable over 12 months of storage following extract preparation. Overall, the present study provides an evidence-based technical/functional rationale for the preparation and control of American bison organ-specific lyophilized extracts to be included in nutraceutical preparations.