Objective To investigate the therapeutic effect of acyclovir and reduced glutathione combined with compound glycyrrhizin on children with infectious mononucleosis (IM) complicated with hepatic insufficiency.Methods A total of 80 children with infectious mononucleosis complicated with hepatic insufficiency admitted to Ji'an First People's Hospital from January 2022 to June 2024 were randomly divided into the control group (treated with acyclovir and reduced glutathione) and the observation group (treated with acyclovir and reduced glutathione combined with compound glycyrrhizin) using a random number table method, with 40 cases in each group. Both groups received continuous treatment for 1 week. The clinical efficacy, symptom improvement, liver function indicators [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGD)], immune indicators, adverse reactions, and disease prognosis between two groups were compared.Results The total clinical effective rate of the observation group (95.00%) was higher than that of the control group (80.00%) (P＜0.05); The time for the disappearance of the triad, restoration of liver function, restoration of atypical lymphocytes, and restoration of liver and spleen function in the observation group were (5.20±1.27) d, (7.82±1.34) d, (8.86±1.54) d, (10.04±2.03) d, respectively, which were shorter than those in the control group [(7.22±1.48) d, (9.26±1.76) d, (10.24±2.02) d, and (12.65±2.67) d], with statistical differences (P＜0.05); The levels of ALT, AST, and GGD in the observation group after treatment were (32.38±4.11) U/L, (29.36±4.44) U/L, and (43.47±7.29) U/L, respectively, which were lower than those in the control group [(40.46±5.25) U/L, (35.36±5.14) U/L, and (52.56±8.47) U/L], with statistical differences (P＜0.05); After treatment, the levels of CD3⁺ and CD8⁺ in the observation group were (66.63±6.25)% and (35.37±4.08)%, respectively, which were lower than those in the control group [(72.76±6.13)% and (44.43±5.17)%]. The levels of CD4⁺ and CD4⁺/CD8⁺ were (38.37±4.96)% and (1.14±0.21)%, respectively, which were higher than those in the control group [(32.37±4.43)% and (0.79±0.18)%], with statistical differences (P＜0.05); The incidence of adverse reactions in the two groups was similar, with no statistically significant difference (P＞0.05); The EBV DNA conversion rate in the observation group (95.00%) was higher than that in the control group (80.00%) (P＜0.05). Conclusion Acyclovir and reduced glutathione combined with compound glycyrrhizin has significant therapeutic effects in children with IM complicated with hepatic insufficiency. It can effectively promote the recovery of clinical symptoms, improve liver function and immune index levels, and does not increase the occurrence of adverse reactions. It can also enhance virus clearance ability, which is beneficial for disease prognosis.