Spectrophotometric methods are used for the development and validation of simultaneous estimation of Atorvastatin calcium and ezetimibe. Method (I) is based on dual wavelength analysis whilemethod (II) is the mean centering of ratio spectra spectrophotometric (MCR) method. In method (I), two wavelengths were selected for each drug in such a way that the difference in absorbance was zero for the second drug. At wavelengths 226.6 and 244 nm EZ had equal absorbance values; therefore, these two wavelengths have been used to determine Atorvastatin calcium; on a similar basis 228.6 and 262.8 nm were selected to determine ezetimibe in their binary mixtures. In method II, the absorption spectra of both Atorvastatin calcium and ezetimibe with different concentrations were recorded over the range 200–350, divided by the spectrum of suitable divisor of both Atorvastatin calcium and ezetimibe and then the obtained ratio spectra were mean cantered. The concentrations of active components were then determined from the calibration graphs obtained by measuring the amplitudes at 215–260 nm for both Atorvastatin calcium and ezetimibe. Accuracy and precision of the developed methods have been tested; in addition, recovery studies have been carried out in order to confirm their accuracy. On the other hand, selectivity of the methods was tested by application for determination of different synthetic mixtures containing different ratios of the studied drugs. The developed methods have been successfully used for determination of Atorvastatin calcium and ezetimibe in their combined dosage form and statistical comparison of the developed methods with the reported spectrophotometric one using F and Student’s t-tests showed no significant difference regarding both accuracy and precision.