There are urgent needs for sensing devices capable of distinguishing between episodes of opioid overdose and nerve agent poisoning. This work presents a wearable microneedle sensor array for minimally invasive continuous electrochemical detection of opioid (OPi) and organophosphate (OP) nerve agents on a single patch platform. The new multimodal microneedle sensor array relies on unmodified and organophosphorus hydrolase (OPH) enzyme-modified carbon paste (CP) microneedle electrodes for square wave voltammetric (SWV) detection of the fentanyl and nerve agent targets, respectively. Such real-time simultaneous sensing provides distinct unique information, along with attractive analytical performance, including high sensitivity, selectivity, and stability, for real-time on-body OPi-OP analysis. The patch represents the first sensing device capable of continuously monitoring fentanyl down to the nanomolar level through a nanomaterial-based multilayered surface architecture. Applicability of the sensor array toward opioids screening is demonstrated for morphine and norfentanyl. Successful OPi-OP detection conducted in a skin-mimicking phantom gel demonstrates the suitability of the device for rapid on-body sensing. Such progress toward continuous minimally invasive transdermal analysis of drugs of abuse and nerve agents holds promise for rapid countermeasures for protecting soldiers, civilians, and healthcare personnel.