Background <p>Hyperthyroidism complicated by liver failure is associated with high mortality, and the optimal treatment strategy remains unclear. We aimed to compare the clinical characteristics of patients who received different treatments for hyperthyroidism and liver failure.</p> Methods <p>This retrospective cohort study included 137 patients diagnosed with hyperthyroidism and Liver failure between January 2013 and December 2022. The patients were treated with methimazole (MMI) plus artificial liver support system (ALSS), radioactive iodine (¹³¹I) plus ALSS, or MMI alone for 24 weeks. Liver and thyroid function were monitored to determine treatment efficacy and potential complications.</p> Results <p>After propensity score matching, no significant differences in treatment efficacy were observed between MMI plus ALSS and MMI alone at discharge (<i>P</i> = 0.425), 12 weeks (<i>P</i> = 0.104), or 24 weeks (<i>P</i> = 0.104). There were also no significant differences in treatment efficacy between ¹³¹I plus ALSS and MMI alone. However, hospital stays were shorter in the MMI and ¹³¹I plus ALSS groups than in the MMI alone group (<i>P</i> = 0.014 and <i>P</i> = 0.010, respectively). The incidence of adverse events did not differ significantly between the groups.</p> Conclusions <p>Our results suggest that ¹³¹I plus ALSS, MMI plus ALSS or MMI are effective in treating hyperthyroidism and liver failure, and that the addition of ALSS reduces recovery times. Therefore, clinicians can select any of these treatment options based on specific patient characteristics.</p>