The excessive prescription of antibiotics has led to an increasing number of antimicrobial resistances, posing a major public health concern. Therefore, the pharmacological research has shifted its focus to the identification of natural compounds that exhibit anti-pathogenic properties without triggering antibiotic resistance. Butyrate has received increasing attention as a promising candidate for the treatment of bacterial infections in the gastrointestinal tract, particularly when antibiotic treatment is contraindicated. This literature survey summarizes recently investigated antibacterial and immunemodulatory effects of butyrate. This survey revealed that butyrate exerts direct antimicrobial effects against distinct strains of Acinetobacter baumannii, Escherichia coli, Bacillus, and Staphylococcus species. In addition, in vitro and in vivo studies confirmed indirect antimicrobial effects of butyrate, which were exhibited via induction of host defensin production as well as by activation of innate and adaptive immune responses. Finally, the synergistic action of butyrate in combination with other antimicrobial compounds results in a striking clearance of bacterial pathogens. In conclusion, butyrate and its derivatives might be considered as promising antibacterial and immune-modulatory agents in order to tackle bacterial infections without antibiotics.