Guayule rubber (GNR) is an alternative source of natural rubber that does not crossreact with Type I latex allergy because it does not contain any proteins which can be recognized by antibodies raised against Hevea brasiliensis allergens. To advance the commercialization of this elastomer and diversify sources of natural rubber, efficient reinforcement of GNR is required to match the physical properties of vulcanized materials made from H. brasiliensise natural rubber in specific products. Superior or comparable reinforcement to that of carbon black N330, was achieved by partial replacement of carbon black with 5 and 10 phr of waste-derived material. Out of several waste-derived fillers tested, micro sized eggshells showed remarkable reinforcing potential for GNR. Hybrid carbon black/micro sized eggshells/GNR composites (up to 20 phr micro sized eggshells), had increased tensile strength, and elongation at break, while maintaining similar values of 300% modulus and hardness to those achieved by carbon black/GNR composites. Hierarchical cluster analysis partitioned the data into six groups of composites having statistically similar properties within each group. Composites containing 5–20 phr of micro sized eggshells were clustered in a separate group due to their unique combination of high tensile strength and flexibility. The superior reinforcement may reflect a combined synergistic reinforcing effect of carbon black particles, which possess a strong polymer-filler interaction, with the formation of a unique network between the GNR and the waste-derived materials, not attained with H. brasiliensis natural rubber.