Biocatalysis in organic solvents (OSs) enables more efficient routes to the synthesis of various valuable chemicals. However, OSs often reduce enzymatic activity, which limits the use of enzymes in OSs. Herein, we report a comprehensive understanding of interactions between surface polar substitutions and DMSO by integrating molecular dynamics (MD) simulations of 45 variants from Bacillus subtilis lipase A (BSLA) and substitution landscape into a “BSLA‐SSM” library. By systematically analyzing 39 structural‐, solvation‐, and interaction energy‐based observables, we discovered that hydration shell maintenance, DMSO reduction, and decreased local flexibility simultaneously govern the stability of polar variants in OS. Moreover, the fingerprints of 1631 polar‐related variants in three OSs demonstrated that substituting aromatic to polar amino acid(s) hold great potential to highly improve OSs resistance. Hence, surface polar engineering is a powerful strategy to generate OS‐tolerant lipases and other enzymes, thereby adapting the catalyst to the desired reaction and process with OSs. Behold, the surface: Investigating the molecular dynamics (MD) simulations of 45 variants from Bacillus subtilis lipase A (BSLA) and 1631 substitutions’ landscape in “BSLA‐SSM” library obtained a comprehensive molecular understanding of interactions between surface polar substitutions and DMSO. The results suggest that surface polar engineering, driven by three determinants, is a promising rational strategy to tailor OS‐tolerant enzymes.