This work describes the development, optimization and validation of a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous analysis of co-administered ranitidine (RAN) and metronidazole (MET) in plasma of healthy human volunteers. A simple protein precipitation procedure using 1 mL acetonitrile was applied to extract both drugs and metoclopramide as an internal standard (IS) from plasma. The chromatographic separation was achieved on a C₁₈ column with isocratic elution of the mobile phase consisting of acetonitrile and 0.1% formic acid (90 : 10, v/v) at a flow rate of 0.35 mL min⁻¹. The positive ionization mode was used for detecting the ions, by observing the pairs of transition m/z 314.82 < 176.06 for RAN, m/z 172.03 < 127.95 for MET and m/z 299.86 < 277.10 for IS. The linearity range was from 5–600 ng mL⁻¹ for RAN and 2–40 μg mL⁻¹ for MET. The method was found to be sensitive and accurate with good simple extraction recovery and matrix effect, according to FDA guidelines for bioanalytical methods. The developed method could be applied for further bioavailability studies that could be useful in therapeutic drug monitoring.