Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) aggregation and oxidative stress, with limited effective therapeutic options. This study evaluated the antioxidant, neuroprotective, and anti-amyloidogenic potential of Ganoderma lucidum, medicinal mushroom rich in bioactive compounds, including triterpenoids and sterols. Antioxidant activity was assessed using the DPPH assay, and neuroprotective effects were examined in Caenorhabditis elegans models (N2 and CL4176). The anti-Aβ potential of selected bioactive compounds was investigated through molecular docking, molecular dynamics simulations, and MM/GBSA analysis, along with ADMET predictions. The extract exhibited strong antioxidant effects, achieving 96.3% scavenging at 0.25 mg/mL. In C. elegans, treatment enhanced survival under oxidative stress by 25% at 0.5 mg/mL (p < 0.01) and delayed Aβ-induced paralysis, with 17.82% of worms remaining active at 68 h. Docking studies identified Epoxyganoderiol C (–7.8 kcal/mol), 5,6-Dihydroergosterol (–7.9 kcal/mol), and Ganoderiol A (–7.7 kcal/mol) as potent Aβ inhibitors, stabilized in molecular dynamics simulations with favorable RMSD, RMSF, Rg, and SASA profiles. MM/GBSA analysis confirmed strong binding affinities for 5,6-Dihydroergosterol, Epoxyganoderiol C, and Ganoderiol A against Aβ, with ΔG_bind values of − 71.66, −56.42, and − 45.45 kcal/mol, respectively. ADMET predictions indicated good drug-likeness, high gastrointestinal absorption, and no toxicity risks. In conclusion, G. lucidum extract demonstrated potent antioxidant and neuroprotective effects, while its bioactive key compounds—Epoxyganoderiol C, 5,6-Dihydroergosterol, and Ganoderiol A—showed favorable binding affinity and stability with Aβ, along with acceptable pharmacokinetic profiles. These findings suggest that G. lucidum and its bioactive constituents may serve as promising natural candidates for AD therapy.