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Simple Summary: Standard chemotherapy is still ineffective in metastatic colon cancer and does not target cancer stem cells (CSCs). The combination of standard cytostatic drugs with natural compounds is considered a promising approach to improving cancer cell sensitivity to treatment. Here, a combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic and CSCs of colon cancer was investigated in vitro. γH2AX+ and Fast-Halo assays were used to evaluate genotoxicity, an annexin-V assay was used to rate the level of apoptosis, and a scratch test was used to assess antimigratory capacity. All combinations improved the genotoxicity of CPT, achieving a better efficacy with CPT-CEL combination in LOVO and CPT-RSV in LOVO/DX cells. No improvement in the pro-apoptotic effect of CPT was observed. Furthermore, higher efficiency in inhibiting cancer cell migration was noted. Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases. [ABSTRACT FROM AUTHOR]