The incidence of infections caused by drug-resistant bacteria has been one of the most serious health threats in the past and is substantially increasing in an alarming rate. Therefore, the development of new antimicrobial agents to combat bacterial resistance effectively is urgent. This study focused on the design and synthesis of 40 novel tetrahydrobenzothiophene amide/sulfonamide derivatives and their antibacterial activities were evaluated. Compounds 2p, 6p, and 6 s exhibited significant inhibitory effects on the growth of bacteria. To assess their safety, the cytotoxicity of the compounds was assessed using human normal liver cells, revealing that compound 6p has lower cytotoxicity. A mouse wound healing experiment demonstrated that compound 6p effectively improved wound infection induced by trauma and accelerated the healing process. Compound 6p holds promise as a potential therapeutic agent for combating bacterial infections.