The polymicrobial biofilm (PMBF) is formed when microbes from multiple species co-aggregate into an envelope made of extra polymeric substances (EPS) that keep the microbes safe from external stresses. The formation of PMBF has been linked to a variety of human infections, including cystic fibrosis, dental caries, urinary tract infections, etc. Multiple microbial species co-aggregation during an infection results in a recalcitrant biofilm formation, which is a seriously threatening phenomenon. It is challenging to treat polymicrobial biofilms since they contain multiple microbes which show drug resistance to various antibiotics/antifungals. The present study discusses various approaches by which an antibiofilm compound works. Depending on their mode of action, antibiofilm compounds can block the adhesion of cells to one another, modify membranes/walls, or disrupt quorum-sensing systems.