Paxlovid (nirmatrelvir/ritonavir) has received endorsement from several guidelines for treating COVID-19 in adults, but its use in children is still uncertain. This study aimed to evaluate the safety and effectiveness of paxlovid in pediatric patients in the pediatric intensive care unit (PICU). A retrospective analysis was performed on children with COVID-19. The children who received paxlovid comprised the paxlovid group; otherwise, they were referred to as the control group. A total of 31 children were enrolled, with 12 and 19 participants assigned to the paxlovid and control groups, respectively. Approximately 35% had received vaccination against the novel coronavirus. The control group exhibited a significantly lower mean age in comparison to the paxlovid group (p < 0.001). However, no significant differences were observed between the groups in terms of other baseline data and biochemical indexes at admission. However, on the fifth day of drug administration, the paxlovid group exhibited a statistically significant decrease in temperature compared to the control group (p < 0.05). Additionally, the paxlovid group exhibited a significantly shorter conversion time to negativity for novel coronary genes in the respiratory tract (9.5 days) compared to the control group (16 days, p < 0.05). The administration of paxlovid did not result in any observed adverse reactions. Merely two patients exhibited a transient elevation in liver enzyme levels. The application of paxlovid in critically ill pediatric patients with COVID-19 can effectively control symptoms and promote virus clearance, demonstrating efficacy and a relatively low-risk profile.