<p>Biofilm development is a survival tactic employed by microorganisms when faced with adverse conditions. Microbes within biofilms display heightened resistance to antibiotics and immune system reactions, complicating clinical treatment. Infections linked to biofilms, which represent 65–80% of human microbial ailments, greatly impact morbidity and mortality rates. Both natural and synthetic small molecules are acknowledged for their ability to combat biofilm formation. Natural extracts and compounds derived from natural products often demonstrate higher effectiveness and fewer adverse effects compared to their chemically produced equivalents. For a long time, natural substances have been utilized to treat various human health issues, with many still in practice today and playing a crucial role in protecting against infectious diseases. This review describes several categories of antibiofilm agents that fall under the broad heading of natural and synthetic small molecules that are stable and reliable. We have attempted to provide an overview of the most promising antibiofilm drugs that are intensively researched and developed. Alongside, to provide future directions for the development of effective antibiotics, several instances have been illustrated to understand the retarding potential against the growth of pathogens. This knowledge can be utilized in combination with other natural antibiofilm substances derived from various sources to enhance therapeutic approaches.</p> Graphical abstract <p></p>