Background: Coronavirus disease-2019 (COVID-19) has become a pandemic around the globe due to the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2), a new variant of the Coronavirus (CoV) family. The rapid transmission of the infectious disease, 135,646,617 positive cases from which 2,930,732 mortality cases were recorded until 11 April 2021. In an emergency, several existing anti-viral, anti-malarial, and anti-HIV drugs have been used on a repurposing basis. However, without proper clinical evidence, it may create several side effects for the patient. Thus, recommending potential and less-toxic regimens at this emergency stage is the most crucial aspect for any physician. Methods: We have hypothesized a combinatorial drug approach against COVID-19 and to select potential combinations from ten anti-HIV drugs and ten vitamin C derivatives were systematically validated using advanced bioinformatic tools. Initially, the chemical structures used as ligands from PubChem and the target protein, SARS-CoV-2 main protease (PDB ID: 6Y84) from the protein data bank were retrieved for this study. Further, assess the potency, toxicity, drug-ability, and pharmacokinetics profiles using several bioinformatics tools, viz., molecular docking by the AutoDock 4.1 software with predicting activity spectra for substances, Molsoft, ProTox, and SwissADME tools. Molecular dynamics simulation was also employed for most potential candidates to assess their binding stability using GROMACS 5.1.4 software. Results: The above computational investigation indicated that ‘darunavir with L-ascorbyl-2,6-dibutyrate or ascorbic acid-2-sulfate’ combinations strongly inhibit the SARS-CoV-2-main protease as a potential treatment option against COVID-19. Mostly, vitamin C derivatives enhanced the anti-COVID activity and might reduce the post-treatment side effects of darunavir in combination. Conclusions: Overall, the present work suggests that bioinformatics tools are suitable for recognizing potential candidates in an emergency, and herein the selected ‘anti-HIV-drug-vitamin c derivatives’ cocktails may potential-cum-fewer toxic regimens against COVID-19 treatment.