Abstract: Objective To investigate the effect of nimodipine tablets combined with donepezil on cerebral small vessel disease (CSVD) cognitive dysfunction and its effect on cognitive function. Methods A total of 88 patients with CSVD cognitive dysfunction admitted to Xinyi People’s Hospital from September 2017 to September 2018 were randomly divided into two groups (n=44 each). The control group was treated with nimodipine tablets, while the study group was treated with nimodipine and donepezil tablets. The total effective rate, adverse reactions and the levels of high-sensitivity C-reacted protein (hs-CRP) and homocysteine (Hcy) before and after treatment were compared between the two groups. Results The total effective rate of the study group was significantly higher than that of the control group (88.6% vs. 72.7%,P<0.05). The incidence of adverse reactions such as blood pressure drop, facial flushing and distention and pain in the head in the study group was 9.1%, which was not significantly different from that of the control group(11.4%) (P>0.05). There were no significant differences in Hcy and hs-CRP levels between the two groups before treatment(P>0.05). After treatment, the levels of Hcy and hs-CRP in the two groups were decreased(P<0.05), and they were lower in the study group than in the control group(P<0.05). Conclusions Nimodipine combined with donepezil is an ideal treatment for CSVD cognitive dysfunction. It can significantly reduce the levels of Hcy and hs-CRP and significantly improve the cognitive function. It is worthy of further clinical application.