Sonobactericide, an antibiotic-free alternative for antibacterial treatment, has proven extraordinary efficiency in preventing and managing biofilm-related bacterial infections. However, the pathophysiological processes underlying biofilm infections are complex. Considering the dysregulated immune-microenvironment associated with these infections, a dual-track strategy that combines ultrasound with immunoregulation presents a more compelling approach. Nanomaterials provide a golden bridge for ultrasound-assisted immunoregulation. The mechanical forces and reactive oxygen species induced by ultrasound-activated nanomaterials can not only inactivate bacteria enclosed in biofilm, but also disrupt dense biofilm architectures, endowing immunoregulators with superior biofilm penetration. Throughout the process of biofilm removal, immunoregulation plays a continuous role by primarily modulating the inflammatory response of macrophages and neutrophils. The activated immune cells are highly effective in eliminating residual bacteria and repairing damaged tissues. Such complementary action mechanism confers significant superiority over traditional antibiofilm therapeutics, particularly in the case of multidrug-resistant biofilm infections that do not respond to antibiotics.