Ultrasound has been explored as a preservation technique that has great potential to extend the shelf life of foods, ensuring food safety while minimizing the decrease in nutritional value and sensory quality compared to the traditional heat treatment. Numerous studies have elucidated the germicidal effect of ultrasound over a wide variety of microorganisms in several liquid foods. This review addresses the mechanism of microbial inactivation by ultrasound as well as and the intrinsic and extrinsic factors that influence its germicidal and inactivating effects. Furthermore, it presents and discusses the results of the application of ultrasound for the microbiological reduction on numerous liquid food matrices, covering the main finding and raising hypotheses on microorganism’s resistance. This paper also discusses the main strategies of combining ultrasound with other techniques to improve the effectiveness of microbiological inactivation, as well as the ultrasonic equipment available on the industrial and laboratory scales. Last, regulation of the use of ultrasound in the food industry is also addressed.