Objectives: Temporomandibular disorder (TMD) involves dysfunction of the temporomandibular joint and associated muscles of mastication causing pain with chewing, limitation of jaw movement, and pain. While the exact pathophysiology of TMD is not completely understood, it is thought that hyperfunction of the muscles of mastication places stress on the temporomandibular joint, leading to degeneration of the joint and associated symptoms. We hypothesize that chemodenervation of the muscles of mastication with IncobotulinumtoxinA (Xeomin) will decrease the stress on the temporomandibular joint and improve pain associated with temporomandibular joint and muscle disorder (TMJD). Methods: Twenty patients were randomized to IncobotulinumtoxinA (170 units) or saline injection of the masticatory muscles. Patient-reported pain scale (0-10) was recorded at 4-week intervals following injection for 16 weeks. Patients who received saline injection initially were assessed for reduction in pain at the first 4-week interval and if still had significant pain were rolled over into the IncobotulinumtoxinA arm. Results: Preinjection pain scores were similar between patients. While there was a statistically significant reduction in pain score in the placebo group one month, there was an overall larger drop in average pain scores in those patients injected with IncobotulinumtoxinA initially. All patients initially injected with placebo crossed over into the IncobotulinumtoxinA group. Similar results were seen when examining the composite masticatory muscle tenderness scores. There was no significant change in usage of pain medication. Conclusions: We demonstrate utility of IncobotulinumtoxinA in treating patients with TMD with pain despite pain medication usage and other conventional treatments.