AIM: To examine the impact of Angong Niuhuang pill in conjunction with conventional therapy on the recovery of neurological function in patients with cerebral hemorrhage (ICH) characterized by phlegm-heat internal obstruction, and to evaluate its efficacy in enhancing neurological function, promoting brain tissue repair, and mitigating oxidative stress. Additionally, this study aims to elucidate the potential mechanisms underlying these effects through the AMPK-PGC1α-Nrf2 pathway. METHODS: A total of 130 patients with ICH characterized by phlegm-heat internal closure were recruited and randomly allocated into a control group (receiving conventional treatment) and a study group (receiving Angong Niuhuang pill in combination with conventional treatment) using the random number table method, with 65 cases in each group. Post-treatment assessments included the National Institutes of Health Stroke Scale (NIHSS) score, Glasgow Coma Scale (GCS) score, modified Rankin scale (mRS) score, as well as tissue levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α), and nuclear factor erythroid 2-related factor 2 (NRF2). Additionally, serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), glutathione peroxidase 4 (GPX4), acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), iron ions, tumor volume, brain edema volume, and the incidence of adverse reactions were evaluated. RESULTS: Each group comprised 65 cases. Post-treatment, the NIHSS score (9.97±1.22) and mRS score (2.29±0.33) in the Research Group were significantly lower than those in the Control Group (11.17±1.52 and 2.64±0.45, respectively), with p-values less than 0.05. Additionally, the GCS score for the Research Group (14.57±1.19) was notably higher compared to the control group (13.18±1.05) (P<0.05). After treatment, the expressions of AMPK ［(3.34±0.81) ng/mL］, PGC1α ［(2.30±0.67) ng/mL］ and NRF2 ［(3.72±0.85) ng/mL］ in the tissues of the group were higher than those of the control group ［(2.63±0.65) ng/mL, (1.83±0.70) ng/mL, (2.91±0.96) ng/mL］ (P<0.05). After treatment, the levels of serum SOD ［(98.76±6.67) U/mL］ and IL-10 ［(40.37±5.61) pg/mL］ in the research group were higher than those in the Control group group ［(89.65±6.89) U/mL, (35.69±4.65) pg/mL］ (P<0.05); the serum levels of MDA ［(3.36±0.62) nmol/mL］, ROS ［(126.35±23.74) U/mL］, TNF-α ［(17.22±2.07) pg/mL］ and IL-6 ［(33.37±3.76) pg/mL］ in the group were lower than those in the control group group ［(3.76±0.83) nmol/mL, (159.85±26.67) nmol/mL, (19.15±2.34) nmol/mL, (41.26±4.91) nmol/mL］ (P<0.05). After treatment, the serum GPX4 level in the Research Group ［(9.87±1.25) ng/mL］ was higher than that in the control group ［(8.16±1.12) ng/mL］ (P<0.05). The serum levels of ACSL4 ［(8.74±1.45) ng/mL］ and iron ion ［(27.44±3.35) μmol/L］ in the study group were lower than those in the control group (10.12±2.11) ng/mL, (30.46±3.17) μmol/L］ (P<0.05). After treatment, the hematoma volume ［(6.46±1.13) mL］ and brain edema volume ［(11.47±1.76) mL］ in the research group were better than those in the Control group ［(8.71±1.02) mL, (3.41±2.04) mL］ (P<0.05). CONCLUSION: The combination of Angong Niuhuang pill with conventional treatment demonstrates significant efficacy in improving neurological function, promoting brain tissue repair, and alleviating oxidative stress, thereby exhibiting high application value in clinical practice.