In the study, we retrospectively reviewed cases of patients with acute mushroom poisoning admitted to seven hospitals from May 2016 to May 2021. In total, we analyzed 153 acute mushroom poisoning cases. Of these patients, 135 survived and 18 died; no correlation of Ganoderma lucidum treatment with in-hospital mortality was observed (odds ratio = 1.598, P = 0.589). We further analyzed 61 patients who survived with liver injury according to whether they were treated with G. lucidum. Both length of hospital stay and hospitalization expenses in the G. lucidum treatment group were significantly lower than the control, with values of 6.69 ± 3.98 days vs. 9.27 ± 5.30 days (t = 2.174, P = 0.034) and 16,336.49 ± 12,615.76 CNY vs. 27,540.08 ± 23,709.57 CNY (t = 2.382, P = 0.020), respectively. Moreover, cases with a blood purification treatment time > 48 h of the G. lucidum group were significantly less than that of the control (30% vs. 69.23%; χ2 = 4.891, P = 0.027). As a result, G. lucidum seems to be a beneficial treatment in acute mushroom poisoning with liver injury.