Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly transmissible, positive-sense, single-stranded RNA virus responsible for the COVID-19 pandemic. SARS-CoV-2 entry into host cells is mainly mediated by the interactions between viral glycoprotein spike (S protein) and cell receptors, especially the angiotensin-converting enzyme 2 (ACE2), which are both highly glycosylated. Therefore, carbohydrate binding agents such as lectins may represent potential candidates to abrogate virus infection. Lectins are proteins found in different organisms, such as plants and algae, with high affinity for glycans. They have anti-cancer, pro-inflammatory, and anti-microbial properties, and can therefore potentially inhibit viral entry and release by binding to glycosylated residues on viral surfaces. Here we evaluated the in vitro anti-SARS-CoV-2 activity of a lectin isolated from seeds of Vatairea macrocarpa , hereafter called VML. This lectin inhibited SARS-CoV-2 with selectivity index (SI) of 74.4, with a strong inhibition in early stages of viral infection but also protected cells from infection and presented post-entry inhibition. VML also showed strong activity against the Delta and Omicron variants. Further, in a competing assay, the presence of galactose resulted in the complete lack of anti-SARS-CoV-2 activity by VML, recovering virus titres similar to the untreated control. Our findings show that VML lectin possess strong activities against SARS-CoV-2, potentially through glycan-dependent mechanisms that interfere with early stages of viral infection, representing potential candidates for the development of novel antiviral drugs.