Background: In the Democratic Republic of the Congo (DRC), decentralized access to disease-modifying therapies for sickle cell anemia remains fragmented. This study characterizes the baseline anthropometric, clinical, and laboratory profiles of young homozygous SS adults followed in Mbuji-Mayi, a remote under-resourced area, to identify simple and accessible surrogate markers for clinical monitoring. Methods: A descriptive and analytical cross-sectional study was conducted from February to April 2026 in Mbuji-Mayi, DRC. We included 58 stable sickle cell patients (HbSS, aged 15–40 years) and 58 healthy age- and sex-matched controls. Multivariate logistic regression analysis was restricted to 56 homozygous SS patients with complete data to identify independent predictors associated with phenotypic severity, defined according to international standards as a clinical burden exceeding 3 vaso-occlusive crises (VOC) per year. Results: The overall mean age was 20.6 ± 4.5 years. HbSS patients exhibited severe chronic wasting compared to controls (median BMI: 17.8 vs. 19.6 kg/m²; p < 0.001), structural relative auscultatory hypotension, and baseline resting hypoxemia (mean SpO₂: 95.5% vs. 97.9%; p = 0.002). Somatic symptoms such as palpitations (60.34%) and dyspnea (41.40%) predominated significantly in sickle cell patients. The average annual clinical burden included 4.3 ± 3.5 VOC episodes and 1.1 ± 1.4 blood transfusions. The fully adjusted multivariate model demonstrated that resting peripheral capillary oxygen saturation (SpO₂) was the primary independent protective factor against severe clinical phenotypes (aOR = 0.75; 95% CI: 0.57–1.00; p = 0.047). Body Mass Index (BMI) displayed a major protective trend approaching statistical significance (aOR = 0.72; 95% CI: 0.51–1.00; p = 0.053). Age did not exert a significant independent influence (aOR = 1.17; p = 0.063), while hemoglobin levels and reticulocyte counts lost statistical significance (p > 0.05). Conclusion: Tissue hypoxemia at rest and nutritional depletion dictate the clinical expression of phenotypic severity among homozygous SS adults in remote low-resource areas. Non-invasive monitoring of resting SpO₂ and BMI provides simple, accessible, and high-utility surrogate markers to guide risk stratification and optimize supportive care in decentralized settings.