The COVID-19 pandemic stimulated the widespread use of traditional medicinal plants in Brazil, particularly in regions with limited access to healthcare and approved therapies. In this context, medicinal plants became accessible alternatives for symptom management and disease prevention, highlighting the value of traditional health systems as sources of biologically relevant species for further investigation. This study documented medicinal plants used to prevent and treat COVID-19 in São Luís, Maranhão, Brazil, and evaluated the inhibitory activity of Uncaria tomentosa (Willd. Ex Schult)extracts, the most frequently cited species, against the SARS-CoV-2 RBD:ACE2 interaction. An ethnopharmacological survey was initially conducted with 400 participants between November 2022 and March 2023 where a total of 38 medicinal ethnospecies were reported, with an overall prevalence of medicinal plant use of 22.75%. Considering that aqueous preparations were the predominant form of use reported by participants, both aqueous and ethanolic extracts were prepared from the stem bark and leaves of U. tomentosa and evaluated in an in vitro Spike (RBD) inhibition assay. The highest inhibitory activity was observed for stem bark extracts of U. tomentosa, which achieved 98.09% inhibition for the ethanolic extract and 73.40% for the aqueous extract. Preparations obtained from the leaves showed lower activity, with inhibition values of 41.12% and 19.74%, respectively. Chemical profiling was performed by LC-MS/MS combined with molecular networking. Chemical analysis enabled the annotation of oxindole alkaloids and flavonoids previously reported in the literature as exhibiting relevant biological activities in models of viral infections. These findings highlight the ethnopharmacological relevance of U. tomentosa, support its potential as a source of bioactive metabolites, and reinforce the value of ethnopharmacological approaches in identifying promising species for further biological investigation.