Background Hypertension is a risk factor for cardiovascular events. Inflammation plays an important role in the development of essential hypertension. Studies assessing the association between complete blood count-based inflammatory scores (CBCIS) and hypertension are scarce. Therefore, this study aimed to determine the relationship between CBCIS and hypertension among individuals with and without human immunodeficiency virus (HIV). Method This was a cross-sectional study among 344 participants at Serenje District Hospital and Serenje Urban Clinic. We used structured questionnaires to collect sociodemographic, clinical and laboratory characteristics. CBCIS included lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), derived neutrophil-lymphocyte ratio (d-NLR), and differential white blood cells. The primary outcome variable was hypertension defined as systolic and diastolic blood pressure higher than or equal to 140/90 mmHg. Logistic regression was used to estimate the association between hypertension and CBCIS in statistical package for social science (SPSS) version 22.0. Results The participants had a median age of 32 years (interquartile range (IQR) 24–42) and 65.1% (n = 224) were female. The prevalence of hypertension was 10.5% (n = 36). Among those with hypertension, 55.6% (n = 20) were female and 44.4% (n = 16) were male. The CBCIS significantly associated with hypertension in people living with HIV (PLWH) was PLR (adjusted odds ratio (AOR) 0.98; 95% confidence interval (CI) 0.97–0.99, p = 0.01) while in people without HIV, AMC (AOR 15.40 95%CI 3.75–63.26), ANC (AOR 1.88 95%CI 1.05–3.36), WBC (AOR 0.52 95%CI 0.31–0.87) and PLR (AOR 0.98 95%CI 0.97–0.99) were the factors associated with hypertension. Compared to people without HIV, only WBC, ANC, NLR, and d-NLR were good predictors of hypertension among PLWH. Conclusion Our study indicates a notable HIV-status driven association between CBCIS and hypertension, suggesting the use of CBICS as potential biomarkers for hypertension risk with substantial implications for early detection and preventive measures.