Aim: This study evaluated the effect of Ganoderma lucidum on selected biochemical indices for cardiometabolic risk. Study Design: Case-control study. Place and duration of Study: This study was carried out in the Department of Medical Laboratory Science, Babcock University between December, 2018-May, 2019. Methods: The study included 32 female guinea pigs which were assigned into 4 groups (A-D) with 8 in each group. Group A animals served as control, group B animals received only monophasic combined oral contraceptives (COC), group C animals received monophasic COC and 50mg/kg of G. lucidum, group D animals received monophasic COC and 100 mg/kg of G. lucidum. All the test animals received their treatment once daily through oral gavage for 12 weeks. All animals were sacrificed 24 hours after the last dose was given to the test groups. Blood sample was collected via cardiac puncture. Lipoprotein-associated phospholipase-A2 (Lp-PLA2), high sensitive C reactive protein (hsCRP), insulin, insulin-like growth factor-1 (IGF-1), fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC) and high density lipoprotein-cholesterol (HDL-C) were determined using spectrophotometric methods and ELISA as appropriate. HOMA-IR was calculated using homeostasis model assessment index. Data obtained were statistically analyzed using ANOVA, post hoc, all values were expressed as mean±standard deviation. P value less than 0.05 was considered significant. Results: We observed that groups B (25%) and C (25%) animals had significantly higher levels of hsCRP, LpPLA2, TC, TG, LDL, FBG, IGF-1 and HOMA-IR when compared with groups A (25%) and D animals (25%) (p<0.05), however there was no significant statistical difference when groups B and C were compared. Also we observed higher levels of HDL in groups C and D animals when compared with groups A and B animals but not significant statistically. Conclusion: The use of G. lucidum stymies the development of COC-induced cardiometabolic syndrome in a dose-dependent manner.