Coronavirus disease (COVID-19) is a viral disease caused by the SARS-CoV-2 virus and is becoming a global threat again because of the higher transmission rate and lack of proper therapeutics as well as the rapid mutations in the genetic pattern of SARS-CoV-2. Despite vaccinations, the prevalence and recurrence of this infection are still on the rise, which urges the identification of potential global therapeutics for a complete cure. Plant-based alternative medicine is becoming popular worldwide because of its higher efficiency and minimal side effects. Yet, identifying the potential medicinal plants and formulating a plant-based medicine is still a bottleneck. Hence, in this study, the systems pharmacology, transcriptomics, and cheminformatics approaches were employed to uncover the multi-targeted mechanisms and to screen the potential phytocompounds from significant medicinal plants to treat COVID-19. These approaches have identified 30 unique COVID-19 human immune genes targeted by the 25 phytocompounds present in four selected ethnobotanical plants. Differential and co-expression profiling and pathway enrichment analyses delineate the molecular signaling and immune functional regulations of the COVID-19 unique genes. In addition, the credibility of these compounds was analyzed by the pharmacological features. The current holistic finding is the first to explore whether the identified potential bioactives could reform into a drug candidate to treat COVID-19. Furthermore, the molecular docking analysis was employed to identify the important bioactive compounds; thus, an ultimately significant medicinal plant was also determined. However, further laboratory evaluation and clinical validation are required to determine the efficiency of a therapeutic formulation against COVID-19.