The current treatment of choice for polyarthralgia in Crohn's disease consists of disease-modifying agents and anti-inflammatory therapy, such as anti-tumor-necrosis-factor alpha inhibitors like infliximab. However, here we report the case of a patient with longstanding Crohn's disease, who developed polyarthritis after receiving only one dose of infliximab. A 57-year-old male with a past medical history of Crohn's disease and stage 1 colon cancer was admitted to our hospital with complaints of polyarticular polyarthralgia, stiffness, and restriction of movements at the joints that started one day prior to admission. It initially began in bilateral wrists, impairing him to hold objects, then spread to bilateral ankles, causing him to fall, and finally affected his jaw, leading to inability to chew or articulate. He received the first dose of infliximab infusion 10 days prior to admission. Labs revealed elevated anti-infliximab antibody levels with low infliximab drug levels. He was treated with steroids, azathioprine, and non-steroidal anti-inflammatory drugs with discontinuation of infliximab. On follow-up, he was initiated on vedolizumab for maintenance of Crohn's disease and did not develop similar complaints again. Our patient had neither had pre-medication antibodies and positive anti-nuclear antibody, nor received the medication for a long duration as proposed in various studies. He developed severe symptoms affecting the majority of axial skeleton from face to feet just after receiving one dose of infliximab. This suggests that further studies in regard to pathophysiological mechanisms and the dose and duration in correlation to symptoms need to be performed for a better understanding of this disease entity.