Creating a sensor that can concurrently monitor multiple therapeutic drugs in complex media is a challenging yet essential endeavor. This study presents a novel biomolecule-free electrochemical platform for simultaneous and highly selective detection of methotrexate (MTR) and paracetamol (PRC) in various matrices, including pharmaceutical formulations, simulated blood samples, and water samples. The platform utilizes a multi-layered petal-shaped black phosphorous structure supported on 3D graphene, along with bio-synthesized copper nanoparticles (BP-3DGp@BCuN). Prior to the sensing study, the as-prepared BP-3DGp@BCuN nanocomposite was characterized using FESEM, EDX, FTIR, UV, XPS, Raman spectroscopy, BET, and XRD. Electrochemical studies of BP-3DGp@BCuN nanocomposite reveal a considerable enhancement of the current compared to pure BP or 3DGp. The petal-shaped black phosphorous comprising of 3DGp and BCuN provides a larger surface area, effective mass transport, and more active sites for the attachment of the target analytes that amplified the current signals and detection sensitivity. Furthermore, computational analysis proves that the BP-3DGp@BCuN nanocomposite has strong interaction with the target MTR and PRC compared to other modifiers. Under optimized conditions, the proposed sensing method shows a linear detection range of 0.05–70 µM and 0.5–210 µM with limit of detection (LOD) values of 0.045 nM and 0.36 nM, with high sensitivity of 37.40 and 14.94 μA μM−1 cm−2 for PRC and MTR respectively. The real-life application of the present sensor was examined in pharmaceutical formulations, simulated blood, and water samples.