Background and Objectives The Alberta Stroke Program CT Score (ASPECTS) is a widely used rating system for assessing infarct extent and location. We aimed to investigate the prognostic value of ASPECTS subregions' involvement in the long-term functional outcomes of acute ischemic stroke (AIS). Materials and Methods Consecutive patients with AIS and anterior circulation large-vessel stenosis and occlusion between January 2019 and December 2020 were included. The ASPECTS score and subregion involvement for each patient was assessed using posttreatment magnetic resonance diffusion-weighted imaging. Univariate and multivariable regression analyses were conducted to identify subregions related to 3-month poor functional outcome (modified Rankin Scale scores, 3-6) in the reperfusion and medical therapy cohorts, respectively. In addition, prognostic eficiency between the region-based ASPECTS and ASPECTS score methods were compared using receiver operating characteristic curves and DeLong's test. Results A total of 365 patients (median age, 64 years; 70% men) were included, of whom 169 had poor outcomes. In the reperfusion therapy cohort, multivariable regression analyses revealed that the involvement of the left M4 cortical region in left-hemisphere stroke (adjusted odds ratio [aOR] 5.39, 95% confidence interval [CI] 1.53-19.02) and the involvement of the right M3 cortical region in right-hemisphere stroke (aOR 4.21, 95% CI 1.05-16.78) were independently associated with poor functional outcomes. In the medical therapy cohort, left-hemisphere stroke with left M5 cortical region (aOR 2.87, 95% CI 1.08-7.59) and caudate nucleus (aOR 3.14, 95% CI 1.00-9.85) involved and right-hemisphere stroke with right M3 cortical region (aOR 4.15, 95% CI 1.29-8.18) and internal capsule (aOR 3.94, 95% CI 1.22-12.78) affected were related to the increased risks of poststroke disability. In addition, region-based ASPECTS significantly improved the prognostic efficiency compared with the conventional ASPECTS score method. Conclusion The involvement of specific ASPECTS subregions depending on the affected hemisphere was associated with worse functional outcomes 3 months after stroke, and the critical subregion distribution varied by clinical management. Therefore, region-based ASPECTS could provide additional value in guiding individual decision making and neurological recovery in patients with AIS.