Introduction: The combination of microbubbles (MBs) and ultrasound (US) is an emerging method for the noninvasive and targeted enhancement of intratumor chemotherapeutic uptake. This method showed an increased local drug extravasation in tumor tissue while reducing the systemic adverse effects in various tumor models. Area covered: We focused on preclinical and clinical studies investigating the therapeutic efficacy and safety of this technology for the treatment of colorectal, pancreatic and liver cancers. We discussed the limitations of the current investigations and future perspectives. Expert opinion: The therapeutic efficacy and the safety of delivery of standard chemotherapy regimen using MB-assisted US have been mainly demonstrated in subcutaneous models of digestive cancers. Although some clinical trials on pancreatic ductal carcinoma and hepatic metastases from various digestive cancers have shown promising results, successful evaluation of this method in terms of US settings, chemotherapeutic schemes and MBs-related parameters will need to be addressed in more relevant preclinical models of digestive cancers, in small and large animals before fully and successfully translating this technology for clinic use. Ultimately, a clear evidence of the correlation between the enhanced intratumoral concentrations of therapeutics and the increased therapeutic response of tumors have to be provided in clinical trials.