The worldwide use of natural remedies is an alternative therapeutic solution to strengthen immunity, fight, and prevent this disease. The rapid spread of the coronavirus disease worldwide has promoted the search for therapeutic solutions following different approaches. China and Benin have seen the use of natural remedies such as Chinese herbal medicine and local endemic plants as alternative solutions in treating COVID-19. The present study was designed to identify the prevalence of medicinal plant use in four municipalities of Benin most affected by COVID-19 and compare them with traditional Chinese medicine and finally verify the efficacy of the main components of the six plants most frequently used, via in vitro experiments. This study targeting market herbalists and traditional healers was conducted in the form of an ethnomedicinal survey in four representative communities (Cotonou, Abomey-Calavi, Zè, and Ouidah) of southern Benin. The chemical compositions of the six most commonly used herbs were investigated using network pharmacology. Network-based global prediction of disease genes and drug, target, function, and pathway enrichment analysis of the top six herbs was conducted using databases including IPA and visualised using Cytoscape software. The natural botanical drugs involved three medicines and three formulas used in the treatment of COVID-19 in China from the published literature were compared with the top six botanical drugs used in Benin to identify similarities between them and guide the clinical medication in both countries. Finally, the efficacy of the common ingredients in six plants was verified by measuring the viability of BEAS-2B cells and the release of inflammatory factors after administration of different ingredients. Binding abilities of six components to COVID-19 related targets were verified by molecular docking. According to the medication survey investigation, the six most used herbs were Citrus aurantiifolia (13.18%), Momordica charantia (7.75%), Ocimum gratissimum (7.36%), Crateva adansonii (6.59%), Azadirachta indica (5.81%), and Zanthoxylum zanthoxyloides (5.42%). The most represented botanical families were Rutaceae, Lamiaceae, Cucurbitaceae, Meliaceae, and Capparaceae. The network pharmacology of these six herbal plants showed that the flavonoids quercetin, kaempferol, and β-sitosterol were the main active ingredients of the Benin herbal medicine. Chinese and Beninese herbal medicine are similar in that they have the same targets and pathways in inflammation and oxidative stress relief. Mild COVID-19-related targets come from C. aurantiifolia and M. charantia, and severe COVID-19-related targets come from A. indica A. Juss. Cell viability and enzyme-linked immunosorbent assay results confirmed that six major compounds could protect BEAS-2B cells against injury by inhibiting the expression of inflammatory factors, among which quercetin and isoimperatorin were more effective. Docking verified that the six compounds have good binding potential with COVID-19 related targets. These results suggest that Benin herbal medicine and Chinese herbal medicine overlap in compounds, targets, and pathways to a certain extent. Among the commonly used plants in Benin, C. aurantiifolia and M. charantia may have a good curative effect on the treatment of mild COVID-19, while for severe COVID-19, A. indica can be added on this basis.