Pandemics of lethal coronaviruses have created huge challenges to healthcare systems over the last few years. The fast proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) created an urgency of the search for potent antiviral vaccinations and medications to administer and avert the prevalent. Even though there is a variety of therapeutic medicine in various stages of research, traditional medicine provides the necessary immune response to distinct stages of coronavirus disease 2019 (COVID-19) infection. Several antiviral medicines are now being researched against SARS-CoV-2, and some are even being utilized. This includes ritonavir and lopinavir, as well as azvudine and ribavirin, remdesivir and favipiravir. The plant kingdom, which may contain various bioactive compounds with medicinal potential, is relatively unexplored. Researchers have been attempting to examine many natural bioactive chemical compounds identified in different medicinal plants which have the potential to limit the multiplication of the virus since the onset of the pandemic. The macromolecules from plant bioactive source can be applied therapeutically against numerous viral infections with high efficiency and low adverse effects. Likewise, the synthetic medicines and plant based bioactive macromolecules can work together with nonlinear combination effects of two active compounds with similar or correlated outcomes of their perceptible activities, or active compounds with complementary or sequential activities, which is known as the synergistic or combined effect of the drug, can provide desired outcome in treating mutated SARS-CoV-2 to deliver increased antiviral effects against mutated SARS-CoV-2. At the host’s cell membranes, hydroxychloroquine and azithromycin showed synergy as possible competitive inhibitors of SARS-CoV-2. Synergy was also at the heart of a suggestion to combine several deoxynucleosides with 5-fluorouracil, which became ineffectual due to coronavirus detection when taken alone. Aescin, reserpine, phenanthroindolizidines and phenanthroquinolizidines, ethanolic extract, tetra-O-galloyl-β-d-glucose and luteolin, and quercetin derivatives have been reported to show inhibitory effects against SARS-CoV-2 where aescin, reserpine, phenanthroindolizidines, and Phenanthroquinolizidines have shown a promising effect in inhibiting viral replication and the other compounds are being reported for their antiviral activity.