Chalcones are an important class of naturally occurring and synthetic compounds that have attracted considerable attention owing to their wide range of biological and pharmacological activities, including anticancer, antimicrobial, anti-inflammatory, and antioxidant properties. In the present study, a series of methylxanthine-based chalcone derivatives, N-(substituted aryl)acryloyl theophyllines 3(a–e), were synthesized through a Claisen–Schmidt condensation reaction involving aromatic aldehyde derivatives and acetylated theophylline precursors in ethanol under basic or acidic catalytic conditions. The synthesized compounds were purified by recrystallization and subsequently characterized using Fourier Transform Infrared (FTIR) spectroscopy and Proton Nuclear Magnetic Resonance (^1H NMR) spectroscopy to confirm their chemical structures. The antiproliferative potential of the synthesized derivatives was evaluated against the human Hep-2 cancer cell line using the MTT assay. The results demonstrated that several of the synthesized N-(substituted aryl)acryloyl theophylline derivatives exhibited notable cytotoxic and antiproliferative effects, indicating their ability to inhibit cancer cell growth. The observed biological activity suggests that the incorporation of both chalcone and methylxanthine pharmacophores may contribute to enhanced anticancer properties. These findings highlight the potential of the synthesized compounds as promising lead molecules for the development of novel anticancer agents and warrant further pharmacological and mechanistic investigations.