The formation of gas hydrates in offshore subsea lines is a major flow assurance concern for the oil and gas industry. In this work, the thermodynamic hydrate inhibition (THI) effect of doping amino acids (AA) such as glycine (Gly), l‐alanine (Ala), and histidine (His) with classical gas hydrate inhibitors (CHI) such as methanol (Me), ethylene glycol (EG), and sodium chloride (NaCl) have been examined at diverse operating conditions. The experimental tests were carried out using rocking cell assembly [RC‐5] on pure methane gas at different pressure conditions (40–120 bars) using an equal ratio mixture (1:1) of AA and CHI at a low dosage (2 wt%). The computational three‐dimensional molecular models of AA and CHI were generated to examine electric charge distribution within these molecules and cognize the interaction mechanism between methane hydrates and AA. The experimental results indicate that Me and EG can synergize the THI effect of AA at a low dosage of 1 wt%. The AA doped with Me tend to provide better THI effect compared to AA doped with EG and NaCl. The experimental results also show that the doped AA Ala mixtures provide THI effect similar to pure CHI such as Me, EG, and NaCl at low dosage (2 wt%). © 2020 Society of Chemical Industry and John Wiley & Sons, Ltd.