Abstract Biofuel cells show emerging potential as energy‐supply platform by harvesting bioenergy from human biofluids for next‐generation self‐powered transdermal drug delivery systems. Herein, the study proposes the hydrogel‐based microneedle patch as the drug penetration unit within the corneum to drive the large drug molecules’ delivery. Benefiting from the high porosity and swelling capability, the interstitial fluid can be extracted efficiently to the body surface. One biofuel cell is integrated into the microneedle patch with MXene/carbon nanotube functionalized glucose oxidase bioanode. The transdermal currents of 4–5 µA and open‐circuit potential of 0.28 V are collected in in vivo. The transdermal delivery efficiency and releasing rate of ciprofloxacin and insulin are significantly enhanced in vitro and in vivo models, respectively. The theoretical simulations provide detailed insights into the good electron transport and substrate adsorption, glucose replenishment, and drug delivery under electric field, benefiting the development of transdermal drug delivery systems.