This research aims to investigate the potential antidepressant properties of atorvastatin (ATV), fenofibrate (FFB) and their combination and compare them with fluoxetine (FLX) in the chronic mild stress (CMS) model of depression. Adult male wistar rats were assigned at random into 6 groups (n=8). Control group: received Dimethyl sulfoxide (DMSO 0.5%. p.o). CMS-group: received (DMSO 0.5%. p.o). FLX-treated group: received FLX (10 mg/kg/day. p.o). ATV-treated group: received ATV (10 mg/kg/day. p.o). FFB-treated group: received FFB (200 mg/kg/day. p.o). ATV+FFB-treated group: received combination of ATV and FFB. All groups received treatments 24hrs, 5 hrs and 1 h before OFT and AFST. Then after a 14-day washout period, all groups were given the same treatments and exposed to CMS (except control group) for 3 successive weeks. One hour after the last dose, OFT and CFST were conducted. The data showed that the immobility time in CFST, brain MDA, and IL6 levels were significantly elevated in the CMS group than in the control group. While, brain SOD, BDNF, SE and DA levels, were significantly reduced. In contrast to the CMS group, treatment with FLX, ATV, FFB and the combination of ATV and FFB resulted in a significant reduction in immobility time, MDA, and IL6 levels, as well as a significant increase in SOD, BDNF, SE and DA levels except FFB group that showed non-significant difference with CMS group in DA level. In conclusion, ATV, FFB and their combination presented antidepressant-like effect in CMS-induced depression in male rats.