<p>The practical applications of lightweight high-entropy alloys (HEAs) in catalysis and electrochemical sensors are hindered by inadequate chemical stability and catalytic activity. This study presents one groundbreaking synthesis strategy for fabricating Mg_0.3AlVCuZn HEA nanoparticles by integrating histidine/serine-functionalized boron-doped graphene quantum dot (HSB-GQD). Mg²⁺, Al³⁺, V⁵⁺, Cu²⁺ and Zn²⁺ are coordinated with HSB-GQD to Me-HSB-GQD complex,followed by thermal annealing and controlled oxidative post-treatment. The resulting Mg_0.3AlVCuZn shows single-phase octahedral morphology with a small size of about 50&#xa0;nm and dual graphene-oxide shielding. Unique structure fully exposes active sites and enhances structural and chemical stability across acidic/alkaline media, interface electron transfer, and improves the affinity with polar electrolyte. The s-p-d orbital hybridization among Mg/Al (s, p) and V/Cu/Zn (s, d) induces electron redistribution to optimize adsorption energetics and catalytic specificity. Mg_0.3AlVCuZn shows ultrahigh catalytic activity that is more than 2-fold that of Au nanoparticles. The electrochemical sensor with Mg_0.3AlVCuZn exhibits a broad linear range (0.01–100 µM), ultra-low detection limit (0.0057 µM, S/<i>N</i> = 3), and robust selectivity and long-term stability for electrochemical detection of doxorubicin in human urine. This study also offers a generalizable platform for engineering lightweight HEAs with tailored stability and multifunctional efficacy, bridging advances in catalysis, sensing and energy storage.</p> Graphical abstract <p></p>