A method based on on‐line solid phased extraction capillary liquid chromatography‐electrospray ionization‐mass spectrometry (SPE‐capLC‐ESI‐MS) has been developed for the determination of oxomemazine in human plasma. Prior to injection, 0.5 mL of plasma spiked with metronidazole (internal standard) was mixed with ammonium formate buffer and methyl orange, which served as an ion pair reagent for effective chloroform liquid–liquid extraction. The employment of methyl orange as an ion pair reagent doubled the extraction efficiency, as compared to not using methyl orange. In preliminary experiments, conventional LC‐UV instrumentation was employed. However, it was found that employing a capillary column with an inner diameter of 0.3 mm increased the sensitivity by a factor of ∼100, when injecting the same mass of analyte. Incorporating an easily automated reversed phase column switching system with SPE made it possible to inject up to 100 µL of solution, and the total analysis time was 5 minutes. The method was validated in the range 3 to 30 ng/mL oxomemazine, yielding a correlation coefficient of 0.99 (r2). The within‐assay and between‐assay precisions were between 6.7 and 12% and 6.8 and 7.4%, respectively. The method was used to determine the amount of oxomemazine in a healthy female 20 hours after an intake of 1 teaspoon (approximately 1 mL) of the cough syrup Toplexil®, which contains 0.033 g oxomemazine per 100 mL syrup. Oxomemazine was detected, and the concentration was calculated to 2.0 ng/mL plasma.