Background: Curcumin is a major active principle of Curcuma longa. There are more than 1700 citations in the Medline, reflecting various biological effects of curcumin. Most of these biological activities are associated with the antioxidant, anti-inflammatory and antitumor activity of the molecule. Several reports suggest various targets of natural curcumin that include growth factors, growth factor receptor, cytokines, enzymes and gene regulators of apoptosis. This review focuses on the improved curcumin derivatives that target the cancer and inflammation. Methodology: In this present review, we explored the anticancer drugs with curcumin-based drugs under pre-clinical and clinical studies with critical examination. Based on the strong scientific reports of patentable and non-patented literature survey, we have investigated the mode of the interactions of curcumin-based molecules with the target molecules. Results: Advanced studies have added new dimensions of the molecular response of cancer cells to curcumin at the genomic level. However, poor bioavailability of the molecule seems to be the major limitation of the curcumin. Several researchers have been involved to improve the curcumin derivatives to overcome this limitation. Sufficient data of clinical trials to various cancers that include multiple myeloma, pancreatic cancer and colon cancer, have also been discussed. Conclusion: The detailed analysis of the structure-activity relationship (SAR) and common synthesis of curcumin-based derivatives have been discussed in the review. Utilising the predictions of in silico coupled with validation reports of in vitro and in vivo studies have concluded many targets for curcumin. Among them, cancer-related inflammation genes regulating curcumin-based molecules are a very promising target to overcome hurdles in the multimodality therapy of cancer. © 2021 Elsevier B.V., All rights reserved.