The present work describes a developed analytical method based on a colorimetric assay using gold nanoparticles (AuNPs) along with chemometric techniques for the simultaneous estimation of sofosbuvir (SOF) and ledipasvir (LED) in their synthetic mixtures and tablet dosage form. The applied chemometric approaches were continuous wavelet transform (CWT) and least squares support vector machine (LS-SVM). Characterization of AuNPs and AuNPs in combination with the drug was performed by UV–vis spectrophotometer, transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier transform infrared (FTIR) spectroscopy. In the CWT method, the zero amplitudes were determined at 427 nm with Daubechies wavelet family for SOF (zero crossing point of LED) and 440 nm with Symlet wavelet family for LED (zero crossing point of SOF) over the concentration range of 7.5–90.0 μg/L and 40.0–100.0 μg/L with coefficients of determination (R2) of 0.9974 and 0.9907 for SOF and LED, respectively. The limit of detection (LOD) and limit of quantification (LOQ) of this method were found to be 7.92, 9.96 μg/L and 12.02, 30.2 μg/L for SOF and LED, respectively. In the LS-SVM model, the mean percentage recovery of SOF and LED in synthetic mixtures was 98.29 % and 99.25 % with root mean square error of 2.392 and 1.034, which were obtained by the optimization of regularization parameter (γ) and width of the function (σ) based on the cross-validation method. The proposed methods were also applied for the determination concentration of SOF and LED in the combined dosage form, recoveries were higher than 95 %, and relative standard deviation (RSD) values were lower than 0.4 %. The achieved results were statistically compared with those obtained from the high-performance liquid chromatography (HPLC) technique for the concurrent estimation of components through one-way analysis of variance (ANOVA), and no significant difference was found between the suggested approaches and the reference one. According to these results, simplicity, high speed, lack of time-consuming process, and cost savings are considerable benefits of colorimetry along with chemometrics methods compared to other ways.