The presence of swelling clays, namely, montmorillonite and illite-smectite mixed layer clays alike, significantly affects well stimulation processes, such as hydraulic fracturing. In this study, the inhibition potentials of three natural amino acids, namely, glycine, lysine monohydrochloride (lysine MHCl), and methionine, on the swelling properties of swelling clays were evaluated using laboratory and theoretical simulation techniques. Linear swelling tests, rheological analysis, zeta potential measurements, FTIR, and FESEM analyses were employed in this experimental work. COSMO-RS was then utilized theoretically to describe the physics by which the proposed amino acids inhibit the swelling of the clay minerals. The obtained results confirmed the clay stabilizing abilities of the studied amino acids. Glycine reduced the imbibition of water into the clay mineral twice better than KCl (a commonly used clay stabilizer), while methionine and lysine MHCl trailed behind glycine and KCl, respectively. Their clay swelling inhibition potentials were then compared to the base fluid: glycine (35%), KCl (18%), methionine (11%), and lysine MHCl (5%). The COSMO-RS simulation analysis confirmed that the inhibition performance of amino acids is mainly controlled by the following: (1) the activity coefficient (γ) between amino acids with water, (2) the hydrogen bonding energy (E HB ) between the amino acids and water, and (3) the side-chain length (p s ) or surface area of the amino acids. A multiple regression model was also developed using the predicted COSMO-RS properties (γ, E HB , and p s ). The model predictions strongly agreed with the experimental results with percentage errors of less than 0.2%. This study reveals that the unique inhibition potentials of amino acids are mostly dependent on their ability to form strong hydrogen bonds with water and clay minerals and their suitable activity coefficients with the base fluid. However, these unique inhibitive mechanisms vary for each natural amino acid due to their varying side chains. The consideration of amino acids as effective clay stabilizers for hydraulic fracturing activities is, therefore, a step in the right direction for replacing toxic fracturing fluid additives and path-charting the application of greener and cleaner processes for shale gas production.