Silver nanoparticles (AgNPs) have shown a wide range of antimicrobial activities over the last 2 decades, but little is known about their antimalarial activity. Therefore, in the present study, AgNPs were surface functionalized by chalcones to create an efficient bioactive molecular surface that can enhance the antimalarial competency of both chalcones as well as chemically synthesized AgNPs. The AgNPs-conjugated chalcones have been synthesized using a chemical method employing the EDC-NHS coupling method. The characterization of AgNPs and AgNPs-conjugated chalcones was done through various analytical techniques. The SYBR Green I assay was performed for in vitro antimalarial activity, and cell cytotoxicity was done on HeLa cell line with MTT assay to calculate the IC50 and CC50, respectively. Haemolytic effect on fresh RBCs of these nanoconjugates were observed for 3 h and 24 h. AgNPs and AgNPs-conjugated chalcones have spectra at 420 nm and between 350 and 375 nm, respectively. The IC50 values of all the three conjugates for antimalarial activity ranged from 0.30 to 0.80 μg/mL. The present study provides a new method of synthesizing AgNPs-conjugated chalcones. Also, these synthesized conjugates show better antimalarial potential and reduced cellular toxicity compared to bared chalcones under an in vitro culture system. However, a further pre-clinical study on the murine model of malaria along with toxicity parameters is needed to provide more clarity. Graphical abstract: (Figure presented.) © 2024 Elsevier B.V., All rights reserved.