<p>In the prevailing pandemic, the emergence of several variants has created concerns, as none of the vaccines have 100% effectiveness. As a countermeasure to combat the infection of SARS-CoV-2 and its variants and to minimize the morbidity, alternative therapeutics have been prioritized, mainly including phytocompounds. In our recent studies, we have considered polyphenols, such as catechin, curcumin, and 8-Hydroxydihydrosanguinarine (8-HDS), for this purpose and found their tendency to bind to the receptor-binding domain of S-protein, thereby inhibiting viral infiltration into the cell. In the current scenario, with the appearance of multiple viral strains, we have furthered our studies on two highly infectious variants of SARS-CoV-2: D614G and B.1.1.7, commonly identified as the UK variant. Our research incorporates various computational methodologies to decipher the potential role of our previously studied phytocompounds and the curcumin derivative, half-curcumin, inhibiting viral attachment and entry for both D614G and the B.1.1.7 lineage. The physicochemical characterization of the spike (S) protein of the UK variant suggests it is less thermostable, which raises questions about its transmissibility in warmer regions of the globe. All the studied phytocompounds have an immense ability to hinder the S protein interaction towards the human cell receptor ACE2 for both the variants. The half-curcumin has also potential drug suitability, which is confirmed through its characterization of ADME (Physicochemical, Water Solubility, Lipophilicity, Drug-likeness, and Pharmacokinetics) properties, and can be considered as a future therapeutic molecule for anti-COVID-19 drug design.</p> Graphical Abstract <p></p>