Objective. To explore the improvement effect of PERMA model-based nursing intervention plus music therapy (MT) on patients with acute liver failure (AHF) undergoing plasma exchange therapy (PET). Methods. This research included 100 AHF patients treated with PET in our hospital, between January 2020 and December 2021, including 54 cases receiving PERMA model-based nursing intervention plus MT (observation group, OG) and 46 cases receiving routine nursing (control group, CG). Clinical efficacy and liver function (LF) were compared between the groups. Prenursing and postnursing psychology, treatment compliance, sleep, pain, and quality of life were assessed, and patient satisfaction was investigated at discharge. Results. The postnursing overall efficacy showed no evident difference between the groups ( P > 0.05 ). The clinical efficacy was mainly markedly significant (50.00%) in OG and effective (43.48%) in CG. The overall response rate was not statistically different between groups (χ2 = 1.392, P > 0.05 ). OG presented better LF, treatment compliance, and sleep quality after nursing, with milder negative emotions and pain than CG ( P < 0.05 ). A higher patient satisfaction rate was also determined in OG at discharge ( P < 0.05 ). Conclusions. PERMA model-based nursing intervention plus MT can effectively improve the psychological state, treatment compliance, and quality of life of AHF patients with PET and reduce pain sensation, which has promising clinical application value in the future.