Background: At the beginning of the pandemic, the SARS-CoV-2 was perceived as a lower respiratory tract infection, affecting the lung parenchyma predominantly and potentially leading to acute respiratory distress syndrome (ARDS) Objective: This study aimed to demonstrate the laboratory outcomes of liver involvement and clinical manifestation in multisystem inflammatory syndrome (MIS) and Covid-19 in children. Subjects and methods: This cross-sectional case-control study was conducted at the Pediatric Department of Al Mabarra-Tanta Hospital, Health Insurance Authority Hospital. This study included 40 children who divided into two groups: Group I included 20 children affected with COVID-19 who met the Centers for Disease Control and Prevention (CDC) definition of MIS-C condition associated with COVID-19. Group II included 20 of sex- and age-matched children with alternative diseases of MIS due to causes other than COVID-19 (autoimmune disease and other types of infection). Results: Alkaline phosphatase levels were significantly higher in group I compared to group II (325.6 ± 98.6 vs 271.9 ± 45.2 U/L). Total bilirubin and direct bilirubin levels were significantly higher in group I compared to group II. Albumin was significantly lower in group I (p=0.01). According to CT result, the percentage of positive findings was significantly higher in group I (100%) compared to group II (30%) (p < 0.001). Among the specific CO-RAD categories, there were significant differences in the distribution between the groups. Conclusions: The findings emphasized the importance of early recognition of MIS-C by investigation and clinical manifestation. These insights could guide improved diagnosis, management, and treatment strategies for children affected by COVID-19-associated liver complications.