Objectives: miR-142-5p was noted aberrantly expressed and plays important roles in different pathophysiologicalconditions in human. The present study aims to examine the expression of miR-142-5p and its association withclinicopathological factors in a large cohort of patients with colorectal cancer. In addition, the cellular effects ofmiR-142-5p and its interacting targets in colon cancer cells were investigated.Methods: Expression of miR-142-5p in colorectal cancer tissues (n = 125) and colon cancer cell lines wereanalysed using real-time polymerase chain reaction. In vitro assays (cell proliferation, wound healing and colonyformation) were used to study the miR-142-5p induced cellular effects. Western blots were used to examine themodulation of FAM134B, KRAS, EPAS1 and KLF6 proteins expression followed by miR-142-5p expression-ma-nipulation.Results: Significant high expression of miR-142-5p was noted in cancer tissues and cells when compared to thecontrols (p < 0.001). Overexpression of miR-142-5p in patients with colorectal cancer was common (72%; 90/125). miR-142-5p overexpression was associated with cancer in the proximal colorectum and with B-raf positivepatients (p = 0.05). Exogenous overexpression of miR-142-5p resulted in significantly increased cell prolifera-tion, colony formation, and wound healing capacities, whereas inhibition of endogenous miR-142-5p led reducedcancer growth properties. The cellular effects of miR-142-5p were mediated by the modulation of tumour sup-pressor KLF6 expression, as the expression of miR-142-5p and KLF6 protein are inversely correlated in coloncancer cells.Conclusion: High miR-142-5p expression was associated with the biological aggressiveness of cancer. Thus,suppression of miR-142-5p could be a therapeutic strategy for patients with colorectal cancers.