Some Gram-positive and Gram-negative pathogenic species can produce a three-dimensional structured matrix composed of bacteria and extracellular biopolymers, called a biofilm. This can form on abiotic surfaces such as medical devices or on biotic surfaces such as host tissue. Because of this, it has become one of the main virulence factors, responsible for various diseases such as infective endocarditis, urinary tract and bloodstream infections, bacteremia, septicemia, among others. The main problem is that due to biofilm formation, antibiotic resistance has been increasing, and therapeutic options have become limited, so new alternatives capable of attacking biofilm-forming bacteria are being sought. Natural products extracted primarily from plants have been considered perfect candidates as therapies against these microorganisms. Phytochemicals, including polyphenols, have been shown to have an effect against biofilm. In this chapter, current information on the potential of polyphenols and their mechanism of inhibition or eradication against biofilm-producing clinical bacteria is presented.