The effects of different antibiotic treatment regimens on intestinal function and flora distribution in children with extraintestinal infectious diseases are explored. A total of 150 cases of extraintestinal infectious diseases admitted to our hospital from January 2021 to January 2022 and 50 healthy subjects during the same period were selected for the study. These 150 children were randomly divided into cephalosporin group, piperacillin group, and combined group and were successively treated with ceftazidime, piperacillin, and two drug combination regimens. The efficacy of the drug, intestinal microflora, intestinal mucosal barrier function, and incidence of antibiotic‐associated diarrhea (AAD) were compared among the different groups. The experimental results showed that ceftazidime combined with piperacillin can effectively improve the intestinal health of children with extraintestinal infectious diseases but destroy the microecological environment of intestinal flora, affect the intestinal mucosal barrier function, and increase the risk of AAD.