Background <p>The success in managing jaundice depends on identifying underlying cause and implementing effective treatment. In this study, we aimed to identify the etiologies of severe jaundice and evaluated the efficacy of glucocorticoids (GCs) in drug-induced liver injury (DILI) and hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).</p> Methods <p>This is a retrospective study of 460 patients with total bilirubin (TBIL) exceeding 85.5 µmol/L from November 2017 to November 2023. The prognosis of patients with DILI or HBV-ACLF receiving GC therapy or non-GC therapy was evaluated.</p> Results <p>HBV infection and DILI were the two most common causes of sever jaundice (36.96% and 22.17%, respectively). In DILI patients, the time taken for peak TBIL levels to decrease by half and to return to normal in the GC therapy group were significantly shorter compared to that in the non-GC therapy group (6 ± 3 vs. 9 ± 4 days, <i>P</i> = 0.006; 32 ± 10 vs. 42 ± 15 days, <i>P</i> = 0.006, respectively) after balancing the baseline parameters using the propensity score matching (PSM) method. Whether in the overall HBV-ACLF population with TBIL ≥ 85.5 µmol/L or in the subgroup with TBIL ≥ 171 µmol/L, the 90-day mortality was significantly lower in the GC group than that in non-GC group (17.9% vs. 56.3%, <i>P</i> = 0.009; 19.4% vs. 60.0%, <i>P</i> = 0.003, respectively). In addition, GC therapy was identified as an independent predictor for mortality in HBV-ACLF patients with TBIL ≥ 171 µmol/L (Hazard Ratio 0.059, 95% confidence interval 0.012–0.284, <i>P</i> &lt; 0.001).</p> Conclusion <p>GC therapy may be beneficial for DILI patients and specific HBV-ACLF patients with severe jaundice.</p> Clinical trial number <p>Not applicable.</p>