Introduction and importance: Conjoined twin is a rare congenital anomaly characterized by a fusion of certain anatomical structures. Coronavirus-19 (COVID-19) is a new emerging infectious respiratory disease affecting worldwide and potentially leads to acute respiratory distress (ARDS) in children. COVID-19 has reconstructed the healthcare system, including surgical care and decision-making. Case presentation: Herein we describe a surgical separation of 2.5 months old omphalopagus conjoined twins, with one of them (Baby A) presenting COVID-19-associated respiratory distress, as well as the challenges faced during the preparation and the execution of the complex surgical procedure. Clinical discussion: Baby A underwent antiviral therapy, oxygen supplementation, and ventilation in the ICU, while baby B remained stable and confirmed negative for SARS-CoV-2. The separation surgery was conducted after baby A had become clinically stable. Defect closure and reconstruction were accomplished. At one week follow-up, Baby A died of lung infection, while baby B remained well after one year. Conclusion: The complexity of surgical separation requires careful planning by a multidisciplinary team. Surgical separation of conjoined twins during the pandemic era has not been reported much in the literature, more reports are required to provide further insight.