Acetaminophen (paracetamol, PA) is among the most widely used analgesic and antipyretic drugs, necessitating sensitive and reliable monitoring in pharmaceutical and clinical matrices. Although numerous PA sensors have been reported, many rely on complex nanocomposites or multistep fabrication, limiting reproducibility and scalability. Here, a minimalist yet highly efficient sensing strategy is demonstrated by electrodepositing a uniformly nanostructured nickel oxide (NiO) film directly onto a disposable screen-printed carbon electrode (SPCE). This rational single-step deposition yields a catalytically active surface with markedly enhanced electron-transfer characteristics. The resulting NiO/SPCE exhibits a linear response from 1.0 to 9.17 μM and a detection limit of 0.11 μM, outperforming many previously reported metal-oxide-based PA sensors. Morphological characterization confirms the formation of a smooth, compact, and homogeneously distributed NiO layer, while differential pulse voltammetry highlights excellent selectivity, minimal interference from common ions and metabolites, and strong operational stability. Together, these features establish the NiO/SPCE as a reproducible, low-cost, and high-performance platform for the precise determination of PA in pharmaceutical formulations and human fluids, with clear potential for integration into portable point-of-care systems.