To investigate whether transcranial ultrasound stimulation (TUS) could improve post-stroke cognitive impairment (PSCI) and the potential mechanisms through which this can be achieved.Sixty patients with PSCI were selected and randomly divided into a control and observation group, respectively, with 30 cases in each group. Conventional cognitive rehabilitation training combined with TUS intervention was conducted in the observation group, while conventional cognitive rehabilitation training and sham-TUS stimulation were given to patients in the control group.The Mini-Mental State Exam, Modified Barthel Index score, P300 latency, and wave amplitude, as well as the serum brain-derived neurotrophic factor (BDNF) levels, were significantly higher in both groups after treatment compared with those before treatment (P < 0.05), and were significantly higher in the observation group than in the control group (P < 0.05). After treatment, the observation group had significantly higher scores in executive, nomination, attention, language, and delayed recall compared with the control group (P < 0.05).Transcranial ultrasound stimulation combined with conventional cognitive rehabilitation therapy improved the PSCI condition with better efficacy than conventional cognitive rehabilitation therapy only. The mechanism involved may be correlated with the upregulation of BDNF and P300 induced by TUS.