Objective To investigate the clinical effect of alteplase combined with citicoline in the treatment of acute ischemic stroke （AIS）.Methods A total of 124 patients with AIS in our hospital from March 2018 to May 2020 were enrolled in a prospective randomized controlled trial， and they were divided into observation group and control group using a random number table， with 62 patients in each group. In addition to conventional treatment， the patients in the control group were given alteplase， and those in the observation group were given alteplase combined with citicoline； the course of treatment was 2 weeks for both groups. The two groups were compared in terms of clinical outcome and adverse reactions， as well as National Institutes of Health Stroke Scale （NIHSS） score and serum levels of apoptosis-related factors ［soluble Fas ligand （sFasL）， soluble Fas （sFas）， and B-cell lymphoma-2 （Bcl-2）］， miR-124， and miR-21 before treatment and after 2 weeks of treatment.Results The observation group had a significantly higher overall response rate than the control group ［91.94% （57/62） vs 77.42% （48/62）， P<0.05］， while there were no significant differences between the two groups in the incidence rates of adverse reactions during treatment （P>0.05）. Both groups had a reduction in NIHSS score after 2 weeks of treatment， and the observation group had a significantly lower score than the control group （P<0.05）. After 2 weeks of treatment， both groups had reductions in the serum levels of sFasL and sFas， and the observation group had significantly lower levels than the control group （P<0.05）； both groups had an increase in the level of Bcl-2， and the observation group had a significantly higher level than the control group （P<0.05）. After 2 weeks of treatment， both groups had reductions in the serum levels of miR-124 and miR-21， and compared with the control group， the observation group had significantly greater reductions （P<0.05）.Conclusions Alteplase combined with citicoline has a marked clinical effect in the treatment of AIS and can alleviate brain injury and improve neurological function by regulating the expression of apoptotic factors， miR-124， and miR-21.