In medicinal chemistry, privileged structures are frequently used as an effective template for finding new drugs. Chalcone is a typical simple compound that occurs in a wide variety of naturally occurring compounds. Chalcone derivatives are also prepared in large quantities due to their simple synthesis. These natural substances have demonstrated a wide range of intriguing biological behaviors with therapeutic potential for treating several diseases. The primary goal of this review is to provide comprehensive information on chalcone-based hybrids. Previous papers have reviewed their multitarget as well as broad-spectrum biological activities. However, some of these molecular targets are not supported by enough solid evidence. So, the most recent reports on the chalcone mechanisms of action were collected and discussed here.