This retrospective observational study aimed to evaluate the effectiveness and hepatoprotective effects of combination therapy with tocilizumab (TCZ) and total glycosides of peony (TGP) in treating systemic juvenile idiopathic arthritis (sJIA). Among the 119 sJIA patients enrolled, 49 received TCZ combined with TGP (study group) and 70 received TCZ not combined with TGP (control group). We compared clinical characteristics, 5 liver function indices (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase/γ-glutamyltransferase/total bilirubin), transaminase (ALT/AST) Kaplan–Meier curves, and inflammatory indices between the groups. The study group showed significantly lower rates of abnormal ALT, AST, alkaline phosphatase, and γ-glutamyltransferase levels (P < .05). Among patients with abnormal liver function indices, transaminase abnormalities were the most common (87.50%), particularly after the first TCZ administration (44.64%). Analysis of Kaplan–Meier curves for transaminases for different treatment durations indicated significantly lower abnormal rates (ALT/AST > 1 and 3 × upper limit of normal) in the study group (P < .05). The Cox regression model and forest plot identified the group with the highest risk ratio (study group vs control group, hazard ratio = 3.985, 95% confidence interval: 1.997–7.952) as an independent risk factor for transaminase abnormalities. A comparison of therapeutic outcomes revealed a more obvious decrease in the number of patients with abnormal inflammation indices in the study group before and after treatment. Moreover, the erythrocyte sedimentation rate value in the study group at the last follow-up significantly lower than that in the control group (P < .05). The combination of TCZ and TGP effectively reduced inflammation and lowered the incidence of liver injury, suggesting it may be the preferred combination therapy for sJIA.