Bacterial infections are characterized by their rapid and widespread proliferation, leading to significant morbidity. Despite the availability of a variety of antimicrobial drugs, the resistance exhibited by pathogenic microorganisms towards these drugs demonstrates a consistent upward trajectory year after year. This trend can be attributed to the abuse or misuse of antibiotics. Although antimicrobial peptides can avoid the emergence of drug resistance to a certain extent, their clinical application has been hindered by factors such as their high production cost, poor in vivo stability, and potential cytotoxicity. Consequently, there arises an urgent need for the development of novel antimicrobial drugs. Small-molecule amphiphatic antimicrobials have a good prospect for research and development. These peptides hold the potential to address several issues, including the high cost of antimicrobial peptide production, poor in vivo stability, and cytotoxicity. Moreover, they exhibit the capability to overcome bacterial resistance, thereby considerably satisfying market demands and clinical needs. This paper reviews recent research pertaining to small molecule host-defending amphiphatic antimicrobials with cationic amphiphilic structures. It focuses on the design concepts, inherent relationships, drug-like properties, antimicrobial activities, application prospects, and emerging screening methods for novel antimicrobial. This review assumes paramount importance in mitigating the current shortcomings of antimicrobial agents. It also provides potential new ideas and methodologies for the research and development of antimicrobial agents.