Based on our previous work with “pseudostationary-ion exchanger sweeping”, we use this strategy to develop a sensitive, reliable and robust method for the analysis of the newly-FDA approved hepatitis C antiviral drugs namely; sofosbuvir (SOV), daclatasvir (DAC), ledipasvir (LED) and velpatasvir (VEP) in their pure forms and co-formulated pharmaceutical dosage forms using micellar electrokinetic chromatography (MEKC) as a separation method. For the first time, a successful separation of all the investigated compounds was achieved in less than 8 min using a basic background electrolyte (BGE) composed of 25 mmol L−1 SDS + 20% (v/v) ACN (acetonitrile) in 10 mmol L−1 disodium tetraborate buffer (final apparent pH is 9.90). A special focus was given to optimize the composition of the sample matrix to maintain the solubility of the analytes within the sample zone while gaining additional benefits regarding analyte zone focusing. It was found that replacing phosphoric acid (as a sample matrix) with a zwitterionic/isoelectric buffering compound (L-glutamic acid) has a substantial positive impact on the obtained enrichment efficiency. The interplay of other enrichment principles such as the retention factor gradient effect (RFGE) is also discussed. A full validation study is performed based on the pharmacopeial and ICH guidelines. The obtained limits of detection and quantitation are as low as 0.63 and 1.3 μg mL−1; respectively for SOV and DAC and 1.3 and 2.5 μg mL−1; respectively for LED and VEP using UV-DAD as a detection method. The selectivity of the developed method for determination of the studied compounds in their pharmaceutical dosage forms or in the presence of ribavirin (RIB) or elbasvir (ELB), which are other prescribed medications in the treatment regimen of patients with hepatitis C virus infection, is demonstrated. It is shown that with acidic sample matrix and basic BGE, an efficient and precise approach was designed in which analyte adsorption on the capillary wall was minimized while keeping repeatable peak height, peak area and migration time together with the highest possible enrichment efficiency.