Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, with few effective treatment options and substantial associated side effects. As a result, there is growing interest in therapeutic alternatives that reduce toxicity. Natural compounds such as sodium butyrate (NaB), a microbial metabolite of dietary fiber, and bromelain, a proteolytic enzyme from pineapple, have shown individual anticancer properties. However, their combined effect in CRC remains underexplored. This study investigates the synergistic potential of NaB and bromelain in colorectal cancer cell lines, focusing on their ability to inhibit proliferation, induce apoptosis, and modulate key molecular pathways. Findings reveal that co-treatment enhances antitumor activity in vitro, suggesting a promising and safer therapeutic strategy for CRC.