CEST MRI detects complex tissue changes following acute stroke. Our study aimed to test if spinlock model-based fitting of the quasi-steady-state (QUASS)-reconstructed equilibrium CEST MRI improves the determination of multi-pool signal changes over the commonly-used model-free Lorentzian fitting in acute stroke. Multiple three-pool CEST Z-spectra were simulated using Bloch-McConnell equations for a range of T1 , relaxation delay, and saturation times. The multi-pool CEST signals were solved from the simulated Z-spectra to test the accuracy of routine Lorentzian (model-free) and spinlock (model-based) fittings without and with QUASS reconstruction. In addition, multiparametric MRI scans were obtained in rat models of acute stroke, including relaxation, diffusion, and CEST Z-spectrum. Finally, we compared model-free and model-based per-pixel CEST quantification in vivo. The spinlock model-based fitting of QUASS CEST MRI provided a nearly T1 -independent determination of multi-pool CEST signals, advantageous over the fittings of apparent CEST MRI (model-free and model-based). In vivo data also demonstrated that the spinlock model-based QUASS fitting captured significantly different changes in semisolid magnetization transfer (-0.9 ± 0.8 vs. 0.3 ± 0.8%), amide (-1.1 ± 0.4 vs. -0.5 ± 0.2%), and guanidyl (1.0 ± 0.4 vs. 0.7 ± 0.3%) signals over the model-free Lorentzian analysis. Our study demonstrated that spinlock model-based fitting of QUASS CEST MRI improved the determination of the underlying tissue changes following acute stroke, promising further clinical translation of quantitative CEST imaging.