Safe and efficient drug delivery is as important as drug development. Biological barriers, such as cell membranes, present significant challenges in drug delivery, especially for newly developed protein-, nucleic acid-, and cell-based drugs. Ultrasound-mediated drug delivery systems offer a promising strategy to overcome these challenges. Ultrasound, a mechanical wave with energy, produces thermal effects, cavitation, acoustic radiation, and other biophysical effects. Used alone or in combination with microbubbles or sonosensitizers, it breaks biological barriers, enhances targeted drug delivery, reduces adverse reactions, controls drug release, switches on/off drug functions, and ultimately improves therapeutic efficiency. Various ultrasound-mediated drug delivery methods, including transdermal drug delivery, nebulization, targeted microbubble destruction, and sonodynamic therapy, are being actively explored for the treatment of various diseases. This review article introduces the principles, advantages, and applications of ultrasound-mediated drug delivery methods for improved therapeutic outcomes and discusses future prospects in this field.