<b><i>Introduction:</i></b> This study aimed to assess anterior scleral thickness (AST) across diverse scleral meridians and to evaluate the relationship with corneal biomechanical response and several ocular parameters. <b><i>Methods:</i></b> This prospective nonrandomized study comprised 50 eyes of 50 patients (mean age, 29.02 ± 9.48 years). AST was measured meridionally at three scleral locations (1, 2, and 3 mm posterior to the scleral spur) using swept-source optical coherence tomography. A multivariate model was created to associate AST with several ocular parameters. Principal component analysis (PCA) was used to reduce linearly the dimensionality of seven biomechanical input metrics to two significant components, C1 and C2. Two multivariate analyses were performed to associate C1 and C2 with AST and ocular parameters. <b><i>Results:</i></b> AST was thickest in the inferior (581 ± 52 µm) and thinnest in the superior meridian (441 ± 42 µm) when compared to all meridians (<i>p</i> &#x3c; 0.001) and similar in the nasal (529 ± 53 µm) and temporal (511 ± 59 µm) meridians (<i>p</i> &#x3e; 0.05). The sclera exhibited the thinnest point 2 mm posterior to the scleral spur (<i>p</i> &#x3c; 0.001). The AST was significantly linked with axial length, central corneal thickness, and intraocular pressure (<i>p</i> &#x3c; 0.001). The PCA showed that C1 accounts for 53.84%, whereas C2 for the 16.51% of the total variance in the original variables. The C1 model was significantly associated with AST along all meridians (<i>p</i> &#x3c; 0.001). The partial correlation was moderate in the nasal (<i>r</i> = −0.36, <i>p</i> &#x3c; 0.001) and inferior (<i>r</i> = −0.26, <i>p</i> = 0.004) meridians, whereas weak in the temporal (<i>r</i> = −0.14, <i>p</i> = 0.05) and superior (<i>r</i> = −0.15, <i>p</i> = 0.05) meridians. <b><i>Conclusions:</i></b> The relationship between the new biomechanical component and the AST provides the first evidence of the association of AST with the corneal response parameters which should be considered in corneal response interpretation. Tissue thickness varied significantly among meridians supporting the asymmetrical expansion of the ocular globe. The AST was associated with several ocular parameters.