Despite the global effort to recover from the COVID-19 pandemic through vaccine procurements and the development of new treatments, the unpredictable fluctuations of symptomatic cases due to the increase in COVID-19 variants still demand the discovery of additional efficacious antiviral drugs. Cyanobacteria generate a wide array of biologically active secondary metabolites, establishing the domain of cyanotherapeutics. However, the therapeutic applications of cyanobacteria against SARS-CoV-2 are yet to be explored. In this study, 56 cyanobacterial secondary metabolites were screened for in silico inhibitory potential against five main target sites of SARS-CoV-2 involved in viral attachment and replication mechanisms. Top-ranked ligands were then subjected to molecular dynamics (MD) simulation. Pharmacokinetic properties and toxicity predictions were also performed. Of the 56 secondary metabolites molecularly docked, compounds 1–7 showed favorable binding energy ranging from –8.0 to –11.2 kcal/mol against the spike’s ACE2 (angiotensin-converting enzyme 2) and GRP 78 (glucose-related protein 78) receptor-binding domains, 3CLPRO (3-chymotrypsin-like protease), PLPRO (papain-like protease), and RdRp (RNA-dependent RNA-polymerase). Three compounds – scytonemin (1), a bisindole alkaloid dimer; enterobactin (2), and agardhipeptin A (3) – exhibited the highest binding affinities with BEs ranging from –8.2 to –11.2 kcal/mol. Through MD simulations, scytonemin (1) complexed with the spike RBD, 3CLPRO, and RdRp, as well as enterobactin (2) complexed with PLPRO demonstrated dynamic stability. Among the three top-scoring lead compounds, scytonemin (1) exhibited drug-like and favorable ADME properties. Hence, the topscoring compounds from cyanobacteria present as favorable drug prototypes for optimization and in vitro testing against SARS-CoV-2. © 2022, Department of Science and Technology. All rights reserved.