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Ultrasound-mediated method, which can effectively disperse agglomerates or even eliminate agglomeration, has received more and more attentions in industrial crystallization. However, the ultrasound-mediated de-agglomeration mechanism has not been well understood, and no general conclusions have been drawn. In this study, the crystallization and de-agglomeration process of ceftezole sodium agglomerates under ultrasound irradiation were systematically investigated. Kapur function was selected to investigate the de-agglomeration process under different ultrasonic powers. The results revealed that ultrasound could efficiently inhibit agglomeration. Besides, the de-agglomeration of large sized agglomerate particles was found to be easier to occur in comparison with small sized particles due to its higher specific breakage rate. Finally, the de-agglomeration mechanism under ultrasonic irradiation was proposed on the basis of the calculated cumulative breakage functions.