Terminal ileitis is a common condition defined as inflammation of the terminal portion of the ileum, which is typically associated with inflammatory bowel disease (IBD), classically Crohn's disease (CD). However, it can have other etiologies, including drug-induced ones. Isotretinoin is an effective and commonly used treatment for acne vulgaris, presenting multiple adverse effects. There have been discussions over its association with enteric inflammation, particularly over IBD emergence risk. We report a case of a previously healthy 17-year-old female who presented transitory clinical, laboratory, imaging, and endoscopic evidence of distal ileitis, temporally related to extended isotretinoin treatment and mimicking CD. Repeated clinical, laboratory, imaging, and endoscopic reassessment after isotretinoin discontinuation confirmed an almost complete resolution of the condition, avoiding IBD misdiagnosis and specific medication initiation. Our case highlights the differential diagnosis of ileitis as being of critical importance to avoid further unnecessary diagnostic investigations and inadequate treatment. Serial re-evaluation may be of key importance to reach a final diagnosis. Although recent literature suggests that isotretinoin is not associated with an increased IBD risk, our case highlights the possibility of it inducing small bowel injury and inflammation, similar to what has been reported with other drugs.