The aim was to develop and validate a simple, fast, reliable, selective and accurate HPLC method with UV detection for simultaneous determination of atorvastatin, glimepiride and amlodipine in a solution and plasma matrix. The method consisted of a mobile phase containing water, methanol and acetonitrile at 1.58:1:1(v/v%) buffered with triethylamine at pH8.0, a flow rate of 1.5 ml/min and a UV detector at 237 nm wavelength. Different and slight variations were introduced in the mobile phase, pH, wavelength, and column temperature to ensure method robustness in yielding good accuracy and precision. Other parameters such as sunlight sample exposure and acid degradation were evaluated on solutions containing the three drugs. A successful HPLC method was validated and developed to detect and quantify atorvastatin, glimepiride and amlodipine in a solution and plasma matrix, system and method precision were reasonable as RSD% values were below 2%, calibration curves revealed linearity in the range of 0.5-1.5 μg/ml for all the three drugs dissolved in the diluent with R2>0.99. RSD% in the linear range and for each of the calibration curve is between 0.03-0.32 for amlodipine, 0.03-0.36 for glimepiride and 0.18-0.46 for atorvastatin. Accuracy was with %recovery for each drug concentration between 98-102% which was considered as acceptable according to USP guidelines for analytical method validation. Stability tests represented reasonable stability of method for three drugs in both plasma and solutions as the % recovery was between 98-102%. Robustness was reliable as wavelength variation,pH variation, acid /base degradation, temperature changes and acetonitrile change in mobile phase showed RSD% less than 2% for all. The method was selective for the three drugs without any possible interference between excipients present in a tablet and the three drugs. Results indicated the method suitability to be used for determination of amlodipine, glimepiride and atorvastatin simultaneously in two different matrices, diluent and plasma.