Objective: Previous studies revealed that the elevation of serum tumor markers (TMs) can serve as a prognostic indicator for diseases other than cancer, but little is known about its association with acute ischemic stroke (AIS). Based on a series of molecular markers and gene pathways shared in both stroke and cancer, we aimed to investigate whether the elevation of TMs could predict clinical outcomes after AIS. Methods: Patients diagnosed with AIS were enrolled and classified into the elevated TMs group and the non-elevated TMs group according to whether any TMs were elevated or not. Then they were followed up 6 months to assess clinical outcomes. Poor functional outcomes were defined as modified Rankin Scale (mRS) > 2 points. Results: 289 AIS patients were finally enrolled, of which 197 (68.2%) were classified as the elevated TMs group. Patients in the elevated TMs group were more likely (OR = 2.384; p = 0.005) to have poor functional outcomes at follow-up than those in the non-elevated TMs group. However, no specific TM was significantly more elevated than the other TMs in the patients with poor functional outcome. The combination of TMs was more sensitive than individual TM in terms of prognosis prediction. Furthermore, rather than the number of elevated items, whether any TM was elevated or not was the most appropriate discriminator for functional outcomes after AIS. Conclusions: Elevation of TMs may indicate poor functional outcomes after AIS. Consequently, AIS patients with elevated TMs required close clinical monitoring and intensified treatment.