Ziprasidone (ZRS) is among the various antipsychotic drugs indicated for treating schizophrenia. The determination of the pharmacokinetic behavior of this drug is of utmost importance in evaluating its bioavailability. The objectives of the present study are: (1) to develop and validate a sensitive, specific, accurate and precise reverse-phase high performance liquid chromatographic method for quantification of ZRS in the plasma of rats; and (2) to apply the developed method to study the pharmacokinetic profile of ZRS in rats after oral administration. The method uses a C18 (250.0 × 4.6 mm, 5 µm) column and ultraviolet detector with wavelength set at 210.0 nm. The mobile phase is acetonitrile-phosphate buffer (pH 3.6) 28:72% v/v at a flow rate of 1.0 mL/min. The internal standard (IS) is escitalopram. The extraction procedure for ZRS and IS from the biological matrix (plasma) employs liquid-liquid extraction technique using a mixture of methyl tert-butyl ether-dichloromethane (70:30% v/v). The results show good accuracy and precision over a linearity range of 20.0-3,000.0 ng/mL with r(2) ≥ 0.9986. The mean recoveries of ZRS and IS are 79.32 ± 1.16 and 84.10 ± 3.2%, respectively. The method has been successfully utilized to study the pharmacokinetic profile of ZRS in rats after oral administration.