An array of microneedles (MNs) of chitosan‐graphene assembled in porous carbon (CS‐GAPC) nanocomposites has been synthesized and evaluated. The safety of the formulated system has been ensured using detailed in vivo toxicological studies and efficacy has been ensured by evaluating the stimuli (pH and electric field) initiated drug delivery properties. Drug cephalexin has been incorporated in these MNs. In vivo toxicological studies of CS‐GAPC nanocomposite were performed on Sprague rats, using acute dermal and subacute dermal (ADT& SADT) test, histopathological studies, biochemical studies, and AMES tests. ADT and SADT studies showed that median lethal dose (LD50) was found greater than 2000 mg/kg body weight; with no abnormal weight gain and food consumption, during the study period of 28 days. This study showed that administration of CS‐GAPC did not cause any substantial alterations in hematological and biochemical parameters of the animals. Histopathological studies showed no significant changes in the control and CS‐GAPC administered groups. AMES tests reveal that CS‐GAPC nanocomposite is nonmutagenic against the Salmonella thyphimurium strains. No abnormalities were observed in the animal's chromosomal aberrations and clastogenic values when the animals were treated with CS‐GAPC. At acidic pH of 4, the encapsulated drug was completely released, indicating that the drug release from the prepared nanocomposite is pH dependent. An electric field of 5 V showed optimum drug release, as a function of applied electric pulses. A biologically safe drug encapsulation model system is hence projected for smart drug delivery (pH dependent and electric field triggered) using the microneedle approach. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1582–1596, 2019.