In this study, a series of chalcone derivatives (compounds 1-18) were synthesized using 4-fluoroacetophenone and various substituted benzaldehydes. The synthesis involved treating the mixture of 4-fluoroacetophenone and benzaldehyde derivatives in methanol with aqueous NaOH, resulting in the formation of the desired chalcones. These compounds were evaluated for their antihyperglycemic activity using two models: the sucrose-loaded model (SLM) and the streptozotocin (STZ)-induced β-cell damaged diabetic model in male Sprague-Dawley albino rats. The results indicated that several compounds exhibited significant antihyperglycemic activity. Compounds 3, 4, and 10 notably showed substantial activity in both models. Metformin and glibenclamide were benchmarks, with glibenclamide showing the highest activity. This study highlights the potential of certain chalcone derivatives as effective antihyperglycemic agents, providing a foundation for further research and optimization.