This study introduces a novel method for the rapid and efficient detection of paracetamol, leveraging a colorimetric sensing mechanism predicated on the utilization of TMB-MnO2 nanosheets. The interaction of paracetamol with MnO2 is characterized by a selective reaction mechanism, leading to the reduction of MnO2 to Mn2+ ions and consequent attenuation of the oxidase-mimetic activity of MnO2. The developed colorimetric sensor exhibits a linear detection range for paracetamol extending from 5 × 10−4 to 10−2 M, with a lower detection limit quantified at 5.24 × 10−7 M. Empirical assessments conducted to ascertain the influence of potential interferents prevalent in actual samples revealed a negligible impact on the colorimetric sensor. Furthermore, the application of this sensor system to real-world samples demonstrated its capability to detect paracetamol with a notable recovery rate and a relative standard deviation of < 6.65%. This approach manifests significant promise for the efficacious detection of paracetamol in various sample matrices.