Over the last few decades, extensive research has been conducted, yielding a detailed account of thousands of newly discovered compounds of natural origin and their biological activities, all of which have the potential to be used for a wide range of therapeutic purposes. There are multiple research papers denoting the central objective of chalcones, which have been shown to have therapeutic potential against various forms of ischemia. The various aspects of chalcones are discussed in this review regarding molecular mechanisms involved in the promising anti-ischemic potential of these chalcones. The main mechanisms involved in these protective effects are Nrf2/Akt activation and NF-κB/TLR4 suppression. Furthermore, in-silico studies were carried out to discover the probable binding of these chalcones to Keap-1 (an inhibitor of Nrf2), Akt, NF-κB, and TLR4 protein molecules. Besides, network pharmacology analysis was conducted to predict the interacting partners of these signals. The obtained results indicated that Nrf2, Akt, NF-κB, and TLR4 are involved in the beneficial anti-ischemic actions of chalcones. Conclusively, the present findings show that chalcones as anti-ischemic agents have a valid rationale. The discussed studies will provide a comprehensive viewpoint on chalcones and can help to optimize their effects in different ischemia.