Paracetamol (PCM) overdose/abuse because of self-medication is a common occurrence amongst people living in low/middle income countries. The present study was designed to investigate the hypolipidemic of Crepis rueppellii (CR) and Rhamnus staddo (RS) aqueous extracts in acetaminophen (paracetamol)-treated guinea pigs. Forty four male guinea pigs (350-650g) were randomly assigned into eleven groups of four guinea pigs each. Group I served as the control group. Groups II received 2g PCM/kg body weight (BW) alone, Groups III received 2g PCM/kg BW and 100 mg silymarin /kg BW, groups IV received 100 mg CR leave extract /kg BW alone while group V received 200 mg CR leave extract / kg BW alone. In-group VI, were administered with 2g PCM/kg BW and 100 mg CR leave extract /kg BW. Meanwhile, group VII were administered with 2g PCM /kg BW and 200 mg CR leave extract /kg BW. Groups VIII received 100 mg RS extract /kg BW alone while group IΧ received 200 mg RS extract alone /kg BW. In group Χ, guinea pigs were treated with 2 g PCM /kg BW and 100 mg RS extract /kg BW. Meanwhile, guinea pigs in group ΧI were treated with 2g PCM /kg BW and 200 mg RS extract /kg BW. The treatment lasted for seven days after which sera were harvested and assayed for serum lipid indices using standard methods. The obtained results showed that, the aqueous extract of C. rueppellii and R. staddo significant (P<0.05) reduced levels of serum total cholesterol, triglyceride, LDL and glucose in the animal model. However, it was unable to produce significant effect on HDL concentration compare between PCM alone. Data from our study suggest that aqueous leave extracts of CR and RS possesses probable hypolipidemic effects.