A facile green accessibility for the synthesis of novel, distinctly substituted 2H-pyran analogues employing montmorillonite K10 clay as a sustainable catalyst via a one-pot multi-component reaction involving various aldehydes, thiophenol and cyanoacetic acid with acetophenone has been developed. The noteworthy features of the current methodology are short reaction time (1.5-2 h), good yields (70-82%), convenient technique, operational simplicity, ease of work-up, and reusability of the catalyst up to two runs, adhering to green chemistry principles. A spectroscopic assessment validated the structure of all the synthesized products. This multi-component one-pot transformation conveniently forms two new C-C bonds, one C-O bond, one C-S bond, and two new rings with all reactants consumed efficiently. Additionally, all synthesized compounds have been evaluated for anti-cancer activity, and two of them were found to be efficacious against human breast cancer cell line, namely, MDA-MB 231. A green and efficient method has been developed for synthesizing novel 2H-pyran analogues using montmorillonite K10 clay as a catalyst. The method involves a one-pot multi-component reaction and yields high products (70–82%) while adhering to green chemistry principles. The synthesized compounds have shown efficacy against human breast cancer cell line MDA-MB 231. [ABSTRACT FROM AUTHOR]