Functionalization on microbubbles (MBs) is a difficult issue due to their unstable nature. Here we report a fast and versatile method using strain promoted alkyne–azide cycloaddition (SPAAC) click reaction for microbubble functionalization. An azadibenzocyclooctyne (DBCO) group was first introduced to MB surface then an azide group to the desired ligand. Without any initiators or catalysts, essential click ligation occurred within 1 min and majority of reaction completed in 5 min under 37 °C. This fast ligation shortens the microbubble reaction time and preserves essential amounts of microbubbles for further in situ imaging and delivery of therapeutics.