An ultrasonic irradiation-assisted green approach was developed for the facile preparation of xanthenones and chromenopyrimidinediones using copper chromite nanoparticles (CuCr2O4 NPs) as an efficient heterogeneous catalyst. The desired products were formed by a one-pot three-component reaction of aromatic aldehydes, 3,4-methylenedioxyphenol, and C-H activated acidic compounds including dimedone and 1,3-dimethylbarbituric acid. Various aromatic aldehydes extended the scope and generality of the presented route. Using water as green and nonvolatile solvent and ultrasonic irradiation as an innocuous energy resource, high yields of products within a short reaction time increase the current protocol’s economic and environmental superiority. Compounds were evaluated for their antimicrobial inhibition against some selected Gram-positive and Gram-negative bacterial strains. The results showed that the growth of Gram-positive bacteria was highly inhibited by only compounds 5a, 5b, 6d, and 6e, while the rest of test compounds show moderate effects on microbial growth. All test compounds, aside compound 6d, did not display any remarkable growth inhibitory activity against the Gram-negative bacteria. Highlights The present study introduces a ground work for the application prospects of ultrasound-based novel, green, and sustainable method for the preparation of some xanthenone and chromenopyrimidinedione derivatives. Copper chromite nanoparticles have appeared as efficacious and reusable catalyst for ultrasonic irradiation treatment in the synthesis of the above-mentioned compounds. The present study establishes that several synthesized compounds show good antimicrobial effects against the standard Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes and Gram-negative bacterium Serratia marescens. Due to the best of our knowledge for these previously known compounds, this study is the first report of their promising antimicrobial activity.