Curcumin, the dried ground rhizome of Curcuma longa Linn., is known as zerdeçal in Turkish, Haldi in Hindi, turmeric in English, and ukon in Japanese. Many biological active properties of this plant, which is widely used in Asian medicine, are known. Commercially known curcumin, on the other hand, contains 77 % of curcumin, along with demetoxycurcumin and bis-demethoxycurcumin. Curcumin and its derivatives belong to the group of diarylheptanoids. The effects of curcumin and its two other derivatives, which have been the subject of many studies thanks to their unique therapeutic ability, on the Spike protein of the SARS-CoV-2 Omicron variant, which caused the pandemic to be declared at the beginning of 2020, were examined within the scope of this study. According to the results obtained, the binding energies of curcumin, demetoxycurcumin, and bis-demethoxycurcumin to the Spike protein of the SARS-CoV-2 Omicron variant are -6.6, -5.5, and -6.0 kcal/mol, respectively. It was determined that curcumin, demetoxycurcumin, and bis-demethoxycurcumin interact with the Spike protein of the SARS-CoV-2 Omicron variant through hydrogen bonding, electrostatic interactions, and hydrophobic interactions. These biologically active molecules are thought to be agents that can moderately inhibit the Spike protein of the SARS-CoV-2 Omicron variant. In addition, the pharmacokinetic and toxicological properties of these three compounds were calculated with the help of online databases.