The COVID-19 disease is a major problem affecting human health all over the world. Consequently, researchers have been trying to find solutions to treat this pandemic-scale disease. Even if there are vaccines and approved drugs that could decrease the spread of this pandemic, multidisciplinary approaches are still needed to identify new small molecules as alternatives to combat COVID-19, especially those from nature. In this study, we employed computational approaches by screening 17 natural compounds from the tropical brown seaweedSargassum polycystumknown to have anti-viral properties that benefit human health. This study assessed some seaweed natural products that are bound to the PLpro of SARS-CoV-2. By employing pharmacophore and molecular docking, these natural compounds fromS. polycystumshowed remarkable scores for protein targets with competitive scores compared to X-ray crystallography ligands and well-known antiviral compounds. This study provides insightful information for advanced study and further in vitro examination and clinical investigation for drug development prospects of abundant yet underexploited tropical seaweeds.