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Objectives: This study aimed to explore the interactions between microbubbles and microwave ablation (MWA). Methods: The study employed custom‐made phantoms (in vitro) and white New Zealand rabbits (in vivo). MWA was performed with or without microbubbles in the phantoms (2 × 105 particles mL−1) and rabbit livers (intravenous injection of 0.05 mL/kg SonoVue). During the MWA, K‐type thermocouple probes were used to monitor the MWA‐induced temperature increase. Contrast‐enhanced ultrasound imaging (CEUS) was used to monitor and analyze the microbubbles signal intensity. After MWA, the ablation‐zone volumes were evaluated and compared between the groups with and without microbubbles. Results: In both the phantom models and rabbits, microbubbles showed no significant influence on MWA, including the ablation range and MWA‐induced temperature increase. In phantoms and rabbit livers filled with microbubbles, MWA caused the formation of a gradually expanding microbubble‐defect region over the ablation time. An increase in the temperature caused microbubble destruction. Conclusions: Microbubbles had no significant influence on MWA. However, MWA induced the destruction of microbubbles in a temperature‐dependent manner. Thus, the poor thermotolerance of microbubbles is a non‐negligible barrier when using CEUS to monitor the ablation range during MWA in real‐time. [ABSTRACT FROM AUTHOR]