Background/Objectives: Smoking and hypertension are major contributors to cardiovascular diseases, with smoker hypertensives typically presenting with exacerbated health risks. These factors are associated with COVID-19 aggravation, but their cumulative impact in the context of this disease remains understudied. Our hypothesis was that hypertensive smokers display a more vulnerable health profile (versus non-smokers) upon hospital admission for COVID-19. Methods: This exploratory observational study compared the clinical profiles of hypertensive COVID-19 patients depending on their smoking status. Focusing on key cardiometabolic, blood, renal, hepatic, and inflammatory markers, this investigation included 100 hypertensive COVID-19 patients (50 smokers and 50 non-smokers) aged 50 and above. Logistic regression and Spearman’s correlations were used to identify significant predictors and relationships among variables. Results: Hypertensive smokers with COVID-19 were significantly more likely to exhibit higher heart rate (p = 0.047), left atrial size (p = 0.013) and diameter (p = 0.040), left ventricular end-systolic volume (p = 0.036), and interventricular septal thickness (p ≤ 0.001). These patients were also much more prone to display elevated CRP (p = 0.035) and hemoglobin (p = 0.011). The renal profiles of the smokers and non-smokers differed, with the smokers showing a significantly greater likelihood to have high serum urea (p = 0.036), but normal-to-low serum potassium (p = 0.011) and sodium (p ≤ 0.001). Their lipid profile was less favorable, with higher triglycerides (p ≤ 0.001), but lower HDL (p = 0.008). The strongest predictors of smoking status were interventricular septal thickness, triglycerides, and serum sodium. Conclusions: Hypertensive smokers admitted to the hospital with COVID-19 tend to exhibit a more adverse clinical profile, particularly in terms of cardiovascular remodeling, lipid imbalances, renal profile, and inflammation. These findings suggest that smoking exacerbates the effects of hypertension in the context of COVID-19, highlighting the need for more aggressive monitoring and management in this patient group.