Handheld auto-injectors (AIs) provide a convenient method for subcutaneous (SC) administration of therapeutics in clinical settings or at home via a caregiver or self-administration. However, AIs have been limited to low volumes (< 2 mL), partly due to hyaluronan (HA), a glycosaminoglycan that acts as a barrier to bulk fluid flow in the SC tissue. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that temporarily depolymerizes HA to facilitate the dispersion of SC-administered therapeutics and may enhance the use of AIs capable of delivering high volumes. These studies detail the development and preclinical testing of a novel high-volume AI (HVAI) that successfully delivered 10 mL of a representative macromolecule (immune globulin; Ig) co-administered with rHuPH20 in ≤ 30 s (s) in a miniature pig model. Testing of a surrogate AI informed the development of a novel, clinically-ready prototype HVAI. HVAI injections of Ig co-administered with 2,000 U/mL rHuPH20 improved injection site outcomes (back-leakage, bleb size, swelling, induration) and yielded up to 30% faster injection times compared with injections of Ig alone. In a mock clinical study that replicated clinical settings, the HVAI delivered 10 mL of Ig with 4,000 U/mL rHuPH20 with mean (± standard error of the mean) injection durations of 19.8 s (± 0.5) using a thin-wall 25-gauge (G) needle and 30.0 s (± 1.1) using a standard 25G needle. The data presented here demonstrate the feasibility of the prototype HVAI for rapid, high-volume administration of a concentrated biologic with rHuPH20, and will inform future clinical testing.