Background <p>Mechanical circulatory support (MCS) devices have been widely used for managing acute myocardial infarction complicated by cardiogenic shock (AMI-CS). However, their use additionally elevates acute ischemic stroke (AIS) risk. There is insufficient data on the risk of AIS associated with early versus late initiation of MCS in AMI-CS cases. Therefore, this study aimed to assess the timing of MCS initiation associated with the risk of AIS in hospitalizations with AMI-CS.</p> Methods <p>A retrospective data analysis of the National Inpatient Sample (January 2016–December 2020) identified AMI-CS hospitalizations: categorized into early MCS initiation (&lt; 48&#xa0;h) and late MCS initiation (&gt; 48&#xa0;h). The primary outcome was AIS; the secondary outcomes included in-hospital mortality, acute kidney injury (AKI), cardiac arrest, major bleeding, and blood transfusion. The outcomes were compared using logistic multivariate regression and 1:1 propensity score matching analyses between the groups.</p> Results <p>Among 78,405 weighted hospitalizations with AMI-CS receiving MCS, 82.77% (<i>n</i> = 64,895) and 17.23% (<i>n</i> = 13,510) underwent early and late MCS initiation, respectively. Hospitalizations with late MCS initiation had higher risks of AIS (adjusted odds ratio [aOR], 1.46; 95%confidence interval [CI], 1.19–1.79; <i>p</i> &lt; 0.001), AKI (aOR, 1.41; 95%CI, 1.27–1.55; <i>p</i> &lt; 0.001), and major bleeding (aOR, 1.12; 95%CI, 1.01–1.23; <i>p</i> = 0.028). After propensity score matching, late MCS initiation remained associated with increased risks of AIS (aOR, 1.39; 95%CI, 1.08–1.78; <i>p</i> = 0.010), AKI (aOR, 1.37; 95%CI, 1.23–1.53; <i>p</i> &lt; 0.001), and major bleeding (aOR, 1.14; 95%CI, 1.02–1.28; <i>p</i> = 0.027).</p> Conclusions <p>Late initiation of MCS was associated with increased risks&#xa0;of AIS, AKI, and major bleeding.</p>