Ketamine, a dissociative anesthetic and analgesic agent used for both human and veterinary medicine, has recently attracted worldwide attention as a recreational drug popular with clubbers. This may necessitate rapid, simple and reliable techniques for the selective determination of ketamine. In this respect, an α-Keggin polyoxomolybdophosphate:18-crown-6 (PM–CE) molecular assembly has been synthesized and comprehensively investigated as an ionophore in PVC membrane sensors. DOP plasticizer and KTpClPB anionic additive are the optimal plasticizer and additive, respectively. In comparison with sensors based on PM–KT as a cation exchanger and CE as a neutral carrier PVC membranes, PM–CE/KTpClPB membrane based sensors exhibit the best performance characteristics. The sensor displays high sensitivity with a response slope of 59.7 ± 0.5 mV (r² = 0.9994) per decade closer to the theoretical Nernstian value, a wider linear range over 2.6 × 10⁻⁶ to 1.0 × 10⁻² M and a lower detection limit of 7.9 × 10⁻⁷ M. The response time of the sensor is ∼10 s and it can be used for about 8 weeks. The proposed sensor possesses reasonable selectivity over some abused drugs in the illicit market of ketamine and the selectivity coefficients are superior to that of PM–KT cation exchanger membrane based sensors. The reliability of the proposed sensors to assess ketamine in pharmaceutical dosage form resulted in an average recovery of 99.3% with a relative standard deviation (RSD %) of 0.24.