Efficient treatment of chronic lung infections caused by biofilms is a great challenge because of drug tolerance and immune evasion issues. Here, we develop ultrasound-responsive catalytic microbubbles with biofilm elimination and immune activation properties to combat chronic lung infection induced by biofilms. In these microbubbles, piperacillin and FeO nanoparticles form a drug-loaded shell surrounding the air core. Under ultrasound stimulation, the microbubbles can physically disrupt the structure of biofilms and enhance the penetration of both FeO nanoparticles and piperacillin into the biofilm. Then, FeO nanoparticles chemically degrade the biofilm matrix and kill the bacteria with the assistance of piperacillin. FeO nanoparticles can activate the immune response for biofilm elimination by polarizing macrophages into a pro-inflammatory phenotype. These ultrasound-responsive catalytic microbubbles efficiently treat chronic lung infections in a mouse model by combining physical/chemical/antibiotic biofilm elimination and immune activation, thus providing a promising strategy for combating bacterial biofilm infections.