Orientin, a C-glycosyl dietary flavone profusely found in rooibos tea and passion fruit have gained much attention owing to their multiple pharmacological potentials. The present study intends to investigate the anti-proliferative and anti-inflammatory efficacy of Orientin in 1,2-dimethyl hydrazine (DMH) induced colorectal cancer (CRC) in rats. Animals were arbitrarily segmented into six groups and fed with high-fat diet. Group 1 served as control. Group 2 received weekly subcutaneous injections of DMH (20 mg/kg b.w.), for first 15 weeks. Group 3 administered with Orientin (10 mg/kg b.w., i.p.) whereas Groups 4–6 treated with Orientin in three phases, namely initiation (along with DMH), post-initiation (post-DMH injection) and entire period. Orientin ameliorates tumor marker levels significantly (p < 0.05) and reinstates the histological changes induced by DMH. The proliferative markers (PCNA and Ki67) were observed to be suppressed significantly (p < 0.05) in Orientin treated rats. Orientin abrogates (p < 0.05) the inflammatory mast cells and diminishes the expression of pro-inflammatory NF-κB and cytokines (TNF-α and IL-6). It also down-regulates over expression of inflammatory inducible enzymes (iNOS and COX-2) significantly (p < 0.05) and further substantiated by GLIDE XP and QPLD studies. Overall results promptly elucidate the anti-proliferative and anti-inflammatory efficacy of Orientin against CRC. Orientin can be developed as a promising chemotherapeutic agent, on further validation of other molecular mechanisms.