The ternary mixture under study is a recent hepatitis‐C antiviral medicine composed of three new directly acting antiviral drugs, namely, ombitasvir, paritaprevir, and ritonavir. They are co‐formulated as a single‐dose combined tablet dosage form. With more than 170 million infected patients worldwide, a large production scales of antivirals medicine is expected, and hence, new simple and fast methodologies are required to cover millions of analyses that are done routinely in the different pharmaceutical quality control and research laboratories. Ultraviolet spectrophotometry represents sensitive, fast, and cheap tool of analysis in all research and quality control laboratories that can cover the massive quality control of these regimens. However, the simultaneous determination of these three drugs using multivariate chemometric methods represents a high challenge as their spectra are strongly overlapping besides the large difference in their potency within the same tablet. In this research paper, four new different multivariate chemometric methods were developed for their simultaneous determination, namely, classical least square (CLS), principal component regression (PCR), partial least squares (PLS), and genetic algorithm‐partial least squares (GA‐PLS) techniques. The validated methods do not require extraction, separation, or derivatization steps. A comparative study was conducted among the four developed methods. All methods provided satisfactory results, whereas GA‐PLS showed better analytical performance as it had the lowest error with good higher correlation coefficient. The methods were applied in the simultaneous determination of the three drugs in pure form and in their combined tablet dosage form. The comparison confirmed agreement of the values obtained for all techniques.