Purpose Acute ischemic stroke (AIS) is a leading health problem caused by cerebral ischemia/reperfusion (CI/R). This study aimed to unveil the potential clinical value and mechanism of lncRNA CASC15. Patients and Methods The expression of CASC15, miR-338-3p was detected by quantitative real-time PCR (qRT-PCR). The correlations between CASC15 and national institutes of health stroke scale (NIHSS) scores or miR-338-3p were evaluated by Pearson correlation. A receiver operating characteristic (ROC) curve was performed to provide the diagnostic value of CASC15. Cell Counting Kit-8 (CCK-8) and flow cytometer were used to detect the condition of cell viability and apoptosis. The levels of interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA) assay. Results The expression of CASC15 was increased and the levels of miR-338-3p were decreased in AIS patients. A positive association between CASC15 and NIHSS score and an inverse association between CASC15 and miR-338-3p were revealed by Pearson correlation. CASC15 might discriminate AIS patients from healthy people. Silenced CASC15 exerted neuroprotective roles on cell viability, apoptosis, and inflammation via the miR-338-3p/ETS1 axis. Conclusion CASC15 might act as a potential diagnostic biomarker for AIS patients. CASC15/miR-338-3p/ETS1 axis played an essential role in cell viability, apoptosis, and neuroinflammation.