Indole moiety is considered a unique core scaffold that can bind with different types of genes and proteins and also has easy synthetic techniques and exclusive chemical characteristics. These characteristics make indole-based scaffolds a prime probe for medicinal chemistry drug research chemists. Hybridization technique utilizing indole moiety could improve the efficacy, combating drug resistance and lowering side-effects of the final compound. Consequently, many indole and 2-oxoindole-based hybrids have been reported recently and entered pre-clinical and clinical studies. But still, more research efforts are essential for a clear understanding of the cancer origin and drug resistance mechanisms in cancer therapy, in addition to getting more achievements in multitargeting drug therapy by developing more potent indole-based scaffolds in the near future. Behind the promising antiproliferative activities of these indole and 2-oxoindole-based hybrids introduced within this review study, there are four main mechanisms which are protein kinases, DNA topoisomerases, histone deacetylase (HDAC), and tubulin polymerization inhibitory activities. Herein, this review will briefly illustrate the newly synthesized indole and 2-oxoindole-based hybrids along with their multiple mechanisms to display their promising antiproliferative activity, which will be a valuable step for more improvement of drug invention and elimination of drug resistance problems' approaches.