Three simple and affordable UV spectrophotometric methods have been proposed for the simultaneous determination of chlorthalidone and nebivolol in a synthetic mixture, as well as a combined dosage form. Method I use the simultaneous equation methodology and has a linearity range of 5–25 µg/mL for chlorthalidone at 233 nm and 5–90 µg/mL for nebivolol at 280 nm respectively. The linearity ranges for chlorthalidone at 228–238 nm and nebivolol at 275–285 nm were found to be 5–60 and 5–100 µg/mL respectively, using method II, the area under the curve method. The linearity range for method III, the first derivative method, is 10–35 µg/mL for chlorthalidone at 227 nm and 10–35 µg/mL for nebivolol at 275 nm. The two diagnostic plot residuals normal probability plot and residuals versus expected values plot are utilized for the verification of outcome data and found to be optimal for three methods. The method has been validated for accuracy, precision, recovery studies, linearity, specificity, and stability studies according to the International Council of Harmonisation guideline Q2R1. These developed methods have been utilized in routine analysis for the simultaneous determination of chlorthalidone and nebivolol without pre-extraction.