Hormonal contraceptives (HC) are thought to play a role in the pathogenesis of cardiovascular diseases. The study evaluated the use of HC as a primary cause of preeclampsia (PE) among Ghanaians. This study comprised 30 preeclamptic women and 30 healthy normotensive pregnant women with over 20 weeks of gestation at the Comboni Hospital, Ghana using a randomized case-control study. Blood pressure, weight, height, socio-demographics, medical and previous obstetric history were taken and recorded. Blood samples were collected for the estimation of homocysteine and fasting lipids. Estimated foetal weight (EFW) and infant birthweight (BWT) were obtained from maternal records. This study was carried out in 2019. 80.0% of women with PE used the hormonal contraceptive “depot medroxyprogesterone acetate” (DMPA) prior to pregnancy. The use of DMPA was associated with about thirty-fold increase in the odds of developing PE (OR = 29.71, p 0.001). Systolic blood pressure (P 0.001), diastolic blood pressure (P 0.001), triglycerides (P = 0.024), LDL-C (P = 0.026), and homocysteine levels (P 0.001) were significantly elevated in the PE cases than the normal pregnant (NP) women, whilst EFW (P 0.001), BWT (P 0.001) and HDL-C levels (P = 0.001) were significantly reduced in the PE cases when compared to NP women. 50% and 47% of PE cases had intrauterine growth restriction and low birthweight infants, respectively. In conclusion, DMPA use predisposes women to a high risk of developing PE. DMPA could partly contribute to endothelial dysfunction, hyperhomocysteinaemia, dyslipidaemia and excessive weight gain, all of which characterize PE.