Caffeic acid is a plant-derived compound that is classified as hydroxycinnamic acid which contains both phenolic and acrylic functional groups. Caffeic acid has been greatly employed as an alternative strategy to combat microbial pathogenesis and chronic infection induced by microbes such as bacteria, fungi, and viruses. Similarly, several derivatives of caffeic acid such as sugar esters, organic esters, glycosides, and amides have been chemically synthesized or naturally isolated as potential antimicrobial agents. To overcome the issue of water insolubility and poor stability, caffeic acid and its derivative have been utilized either in conjugation with other bioactive molecules or in nanoformulation. Besides, caffeic acid and its derivatives have also been applied in combination with antibiotics or photoirradiation to achieve a synergistic mode of action. The present review describes the antimicrobial roles of caffeic acid and its derivatives exploited either in free form or in combination or in nanoformulation to kill a diverse range of microbial pathogens along with their mode of action. The chemistry employed for the synthesis of the caffeic acid derivatives has been discussed in detail as well.