Colorectal cancer (CRC) remains a formidable global health challenge, spurring the exploration of innovative therapeutic strategies. The mitogen-activated protein kinases (MAPK) pathway has emerged as a promising target due to its pivotal role in cellular processes. The MAPK pathway regulates diverse cellular responses, and its dysregulation is implicated in cancer progression. Genetic alterations in CRC, including KRAS and BRAF mutations, confer growth advantages. Erianin, a natural compound, has shown potential in suppressing MAPK pathway activation by inhibiting CRAF and MEK1/2. This precision approach offers an alternative to conventional MAPK inhibitors, potentially overcoming resistance mechanisms. Novel dual-target inhibitors, simultaneously inhibiting RSK1 and MSK2, exhibit promise in CRC treatment by targeting key components of the MAPK pathway. Furthermore, compounds like 3,3'-Diindolylmethane (DIM) exemplify multifaceted pathway modulation by targeting COX1/2 and ERK1/2, inhibiting patient-derived xenograft colon tumors. Clinical translation of MAPK-targeted therapies faces challenges from intrinsic and acquired resistance mechanisms. Combination strategies, rationalized through drug design, aim to enhance efficacy and expand patient eligibility. In conclusion, the pursuit of MAPK pathway targeting in CRC navigates a complex terrain marked by progress and obstacles. Erianin, dual-target inhibitors, and compounds like DIM introduce innovative avenues for CRC treatment.