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Background: Genetic modifications in the renin-angiotensin aldosterone system (RAAS) have been suggested to play a key role in the pathophysiology of hypertension. The insertion/deletion polymorphism of angiotensin-converting enzyme (ACE) gene phenomenon and its relationship with essential hypertension has not been explored within the Ghanaian population. This study aims to determine the relationship between the ACE I/D polymorphism and the risk of essential hypertension among patients seeking medical attention. Methods: This case-control study was conducted at the Tamale Central Hospital in Ghana. A total of 144 study participants comprising 72 hypertensive patients and 72 normotensive individuals were recruited from May to July 2022. The modified WHO step questionnaire for chronic diseases was used to collect ACE concentrations and electrolytes were estimated and molecular testing conducted using to identify genotypes. To compare continuous variables between two groups and among multiple groups, the Student's t-test and analysis of variance (ANOVA) were used respectively. Genotype and allele frequencies were determined through direct counts, while differences in the distribution of alleles and genotypes between groups were estimated using chi-squared test. Results: The distribution of DD genotype and D allele respectively was 26.4% and 54% in hypertensives and 50% and 72% in normotensives. DD genotype significantly increased the risk of hypertension after adjusting for age and BMI (aOR = 8.52, 95% C.I = 1.22–59.6). In the recessive model, the risk of hypertension increased four times in subjects with the DD genotype (aOR = 4.09, 95% CI = 1.28–13.05). ACE levels were significantly elevated among hypertensives compared to controls, but did not significantly differ between the DD genotype and II+ID genotypes among hypertensives and normotensive subjects. Conclusion: The study shows that the presence of the DD genotype is strongly associated with an increased risk of hypertension in the Ghanaian population. [ABSTRACT FROM AUTHOR]