Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Current therapeutic strategies are accompanied by low success rates and several side effects, representing a relevant clinical problem and requiring the discovery of new and more effective therapeutic alternatives. Ruthenium drugs emerged as one of the most promising metallodrugs due to their high selectivity to cancer cells. In this work, we studied for the first time the anticancer properties and mechanisms of action of four lead Ru-cyclopentadienyl compounds, namely PMC79, PMC78, LCR134 and LCR220, in CRC-derived cell lines. Biological assays were performed in CRC cell lines to evaluate cellular distribution, colony formation, cell cycle, proliferation, apoptosis, motility as well as cytoskeleton and mitochondrial alterations. Our results showed that all compounds displayed high bioactivity and selectivity, as shown by low IC50 concentrations against CRC cells. We observed that all Ru compounds had different intracellular distributions and inhibited to a high extent the clonogenic ability and proliferation of CRC cells. In addition, PMC79, LCR134 and LCR220 induced apoptosis, increased the levels of reactive oxygen species, induced mitochondrial alterations and affected F-actin cytoskeleton organization and cellular motility. A proteomic analysis showed that these compounds induce alterations in several cellular proteins related to the phenotypic alterations induced. Overall, we demonstrated that Ru compounds, in special PMC79 and LCR220, present promising anticancer activity in CRC cells and potential to be used as new metallodrugs for CRC therapy.