The management of metastatic melanoma to the orbit may involve a variety of therapeutic modalities including external-beam radiation, chemotherapy, and varying degrees of surgical resection or debulking. Pembrolizumab is an immunotherapeutic agent that has demonstrated efficacy in the treatment of metastatic melanoma. The authors present a case of metastatic melanoma to the orbit demonstrating profound pseudoprogression within hours of beginning pembrolizumab therapy, with associated mass effect and vision loss. Systemic corticosteroids, orbital external-beam radiation therapy, and a brief interruption in pembrolizumab halted expansion of the orbital lesion and vision loss. This case illustrates that rapid increase in orbital melanoma size, due to acute inflammatory response, may occur after initiation of systemic pembrolizumab therapy. Clinicians should be aware of this pseudoprogression mechanism as a potential cause of vision compromise in metastatic orbital melanoma. Prompt recognition and treatment may be needed to prevent permanent vision loss.