Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the GI tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists and CB1R-/- mice have exacerbated experimental colitis. Therefore we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day DSS colitis model in Balb/c mice. In OM colitis, the CB1R-selective agonist ACEA, and the CB2Rselective agonist JWH-133 reduced (p < 0.05) colon weight gain (Mean ± SE; 82 ± 13, and 47 ± 15% inhibition, respectively), colon shrinkage (98 ± 24 , and 42 ± 12 %, respectively), colon inflammatory damage score (49 ± 11, and 40 ± 12 %, respectively), and diarrhea (58 ± 12, and 43 ± 11 %, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, bid, inhibited (p < 0.05) macroscopic and microscopic scores 46 ± 9 and 63 ± 7%, respectively, while 20 mg/kg, bid, of JWH-133 was required to diminish (p < 0.05) macroscopic and microscopic scores 29 ± 7 and 43 ± 5%, respectively. CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic versus control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model, and reinforce the importance of neuronal activation in intestinal inflammation.