Background: First bite syndrome (FBS) is a rare post-surgical complication resulting in peri-parotid pain after the first bite of meals. Intra-parotid Botulinum toxin A may offer relief for these symptoms. There is no consensus on the optimal dosage, timing to symptom improvement, need for repeat injections, and safety of this treatment. The objective of this systematic review was to assess the efficacy and safety of intra-parotid Botulinum toxin A injection in treating FBS. Methods: The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar were searched from the inception until July 2020. Case reports, case series, prospective and retrospective trials in which patients with post-surgical FBS were treated with intra-parotid botulinum toxin A injection were included. The primary outcome was improvement of FBS symptoms. Secondary outcomes were time to symptom improvement and complications. Risk of bias was assessed with National Institute of Health (NIH) Quality Assessment Tools.Results: Search results yielded 41 studies. Thirty-three articles were excluded after screening titles, abstracts, and full texts, yielding eight studies, from which 22 patients were included. No studies included a control. All studies were of lower quality and had at least moderate risk of bias. The initial botulinum toxin A injection dose ranged from 10-75 U. Time from surgical treatment to injection ranged from 1 month to 3 years. Seven studies, containing 17 patients, reported individual patient outcomes. Clinical improvement was reported in 16 patients lasting between 1-30 months post injection. Eight of 8 (100%) patients receiving at least 40 U botulinum toxin A had symptom improvement. Ten of 22 (45.5%) patients received a second botulinum toxin A injection due to return of pain at a mean of 3.8 months after the first injection. Seven of 22 (38.1%) patients had complete symptom resolution at a mean of 12.1 months. There were no reported injection complications, including: facial paralysis, infection, injection site reaction, and allergic reaction.Discussion: There are no controlled studies comparing intra-parotid botulinum toxin A to observation for FBS. However, botulinum toxin A appears to be a potentially safe, effective treatment.