Campylobacter is a leading cause of bacterial foodborne gastroenteritis worldwide, and poultry are a major source of human campylobacteriosis. The control of Campylobacter from farm to fork is challenging due to emergence of microbial resistance and lack of effective control methods. We identified a benzyl thiophene sulfonamide based small molecule (compound 1) with a minimal inhibitory concentration (MIC) of 100 μM against Campylobacter jejuni 81-176 and Campylobacter coli ATCC33559, good drug-like properties, and low toxicity on eukaryotic cells. Compound 1 was used as a lead for the preparation of 13 analogues. Two analogues, compounds 4 and 8 (TH-4 and TH-8), were identified with better antimicrobial properties than compound 1. TH-4 and TH-8 had a MIC of 12.5 μM and 25 μM for C. coli and 50 μM and 100 μM for C. jejuni, respectively. Cytological studies revealed that both compounds affected C. jejuni envelope integrity. Further, both compounds had no effect on other foodborne pathogens. TH-4 and TH-8 had a minimal impact on the chicken cecal microbiota and were not toxic to colon epithelial cells and chicken macrophages, and red blood cells at 200 µM. Further, TH-4 and TH-8 reduced the Campylobacter load in chicken ceca (up to 2-log reduction) when infected chickens were orally treated for 5 days with 0.254 mg kg-1; as well as against internalized Campylobacter in Caco-2 cells at 12.5 µM and higher. Our study identified two novel specific and safe benzyl thiophene sulfonamide derivatives having potential for control of Campylobacter in chickens and humans.