Over the past few decades, applications of ultrasound (US) in drug delivery have been documented widely for local and site-specific release of bioactives in a controlled manner, after acceptable use in mild physical therapy for tendinitis and bursitis, and for high-energy applications in fibroid ablation, cataract removal, bone fracture healing, etc. US is a non-invasive, efficient, targetable and controllable technique. Drug delivery can be enhanced by applying directed US in terms of targeting and intracellular uptake. US cannot only provide local hyperthermia but can also enhance local extravasations and permeability of the cell membrane for delivery of cell-impermeable and poorly permeable drugs. It is also found to increase the anticancer efficacy of drug against solid tumors by facilitating uniform drug delivery throughout the tumor mass. This review summarizes the mechanism of US; various drug delivery systems like microbubbles, liposomes, and micelles; and biological manifestations employed for improving treatment of cancer, i.e., hyperthermia and enhanced extravasation. Safety issues are also discussed for better therapeutic outcomes of US-assisted drug delivery to tumors. This review can be a beneficial asset to the scientists looking at non-invasive techniques (externally guided) for improving the anticancer potential of drug delivery systems.