The quality of medications is important to maintain the overall health care of patients. This study aims to develop and validate a spectrophotometric method using multivariate curve resolution-alternating least squares (MCR-ALS) with correlation constraint for simultaneous resolution and quantification of selected drugs affecting the central nervous system (imipramine, carbamazepine, chlorpromazine, haloperidol, and phenytoin) in different pharmaceutical dosage forms. Figures of merit such as root-mean-square error of prediction, bias, standard error of prediction, and relative error of prediction for the developed method were calculated. High values of correlation coefficients ranged between 0.9993 and 0.9998 reflected high predictive ability of the developed method. The results are linear in the concentration range of 0.3–5 μg/mL for carbamazepine, 0.3–15 μg/mL for chlorpromazine, 0.5–10 μg/mL for haloperidol, 0.5–10 μg/mL for imipramine, and 3–20 μg/mL for phenytoin. The optimized method was successfully applied for the analysis of the studied drugs in their pharmaceutical products without any separation step. The optimized method was also compared with a reported HPLC method using Student’s t test and F ratio at 95% confidence level, and the results showed no significant difference regarding accuracy and precision. The proposed chemometric method is fast, reliable, and cost-effective and can be used as an eco-friendly alternative to chromatographic techniques for the analysis of the studied drugs in commercial pharmaceutical products.