The 2022 global Mpox epidemic infected almost 100,000 people globally, particularly men who have sex with men (MSM). Despite immunogenicity following vaccination, there is increasing evidence of waning immunity over time, especially in immunocompromised patients. With breakthrough infection becoming more prevalent, knowledge of diagnostic nuances is essential to recognizing and treating this condition. Here, we present a case of breakthrough Mpox infection in a fully vaccinated non-HIV immunocompromised patient taking risankizumab, and review the risk factors, diagnosis, and treatment. To the best of our knowledge, no such case has been presented in the literature previously.