Granulomatous inflammation is a rare but known filler-related complication that may present similarly to an active infectious process with pain, swelling, and erythema. This study describes hyaluronic acid filler-related delayed-onset nodule formation in a pair of 44-year-old and 56-year-old females who were ineffectively treated with numerous attempts of antibiotic regimens, incision and drainage (I&D) procedures, and low-dose hyaluronidase across several months despite multiple negative microbial cultures. After initiation of hyaluronidase therapy dosed to filler-related vascular occlusion guidelines, complete resolution of symptoms was achieved in both patients. These cases emphasize the relevance of considering delayed-onset nodules in the differential for filler complications that are culture-negative and unresponsive to antibiotic treatment and I&D. We propose complete dissolution with higher dosage hyaluronidase as a safe and effective treatment modality with respect to the current lack of defined guidelines for treating this complication.