Microorganisms (pathogenic ones) explore acetylated homoserine lactone (AHL) in their quorum sensing system (a series of cell-to-cell communications) activities to bring about biofilm development and various virulence (factors) processes leading to the onset of microbial infections particularly those driven by bacteria communities. Thus, the key contribution of AHL in the emergence of these infections accords it an essential target for their effective management. While several synthetic quorum sensing system (QSS) inhibitors are available, though lacking adequate effectiveness, phenolic compounds among other metabolites from medicinal plants and/or natural products have been found adequate to combat the excesses of QSS. This chapter appraised the contributions of phenolics as QS modulators from computational and experimental studies achieved when an extensive literature search using keywords such as polyphenols, phenolic compounds, flavonoids, phenolic acids, tannins, coumarins, benzoic acids, lignans, and stilbenes was cross-matched with in silico studies, computational analyses, and anti-infective or anti-QS effect. The search from popular scientific databases such as Google Scholar, Science Direct, PubMed, and Medicine yielded a total of 189 reports from 250 downloaded documents from journal articles, conference proceedings, book chapters, and dissertations/theses. Findings revealed that despite wide classes and abundance of phenolic compounds, very few such as curcumin, capsaicin, gallic acid, resveratrol, phloridzin, gingerol, rosmarinic acid, chlorogenic acid, and catechin have been computationally explored as QS modulators. Hence, a call for more research to identify and explore more or other phenolic compounds is necessary to profile more drug candidates from this group of phytocompounds against common and clinically significant nosocomial infections.