Background: Rotavirus gastroenteritis (RVGE) remains a leading cause of severe infant diarrhea worldwide, with growing evidence supporting the role of the gut microbiome in modulating the disease. However, the interplay between early-life demographic factors, the gut microbiome, and their combined impact on RVGE clinical severity remains inadequately characterized, particularly in specific geographic populations. Aim: We aimed to investigate how demographic determinants shape gut microbiome composition and function in RVGE and how these features relate to clinical severity. Methods: In our comprehensive case–control study of 165 infants (120 RVGE cases and 45 healthy controls, aged 0–12 months), we utilized 16S rRNA sequencing combined with advanced statistical modeling and machine learning to investigate how demographic factors influence microbiome composition and clinical outcomes. Results: RVGE cases exhibited significantly reduced bacterial diversity (Kruskal–Wallis, Static = 14.85, p < 0.001) and distinct patterns, with community structure most strongly associated with dehydration severity (PERMANOVA; R² = 0.15, p < 0.001). Substantial taxonomic alterations were identified characterized by depletion of beneficial commensals including Akkermansia (LDA score = 3.8, p < 0.001), Faecalibacterium (Random Forest AUC = 0.82, p < 0.001), and Bifidobacterium (r = −0.42 with breastfeeding, p < 0.001), alongside enrichment of inflammation-associated taxa such as Escherichia-Shigella (WBC; r = 0.49, p < 0.001, and CRP; r = 0.56, p < 0.001), Streptococcus (LDA score = 4.2, p < 0.001), and Staphylococcus. Proteobacteria was the top potential biomarker of severe outcomes (Random Forest AUC = 0.85), with abundance positively correlated with systemic inflammation (CRP: r = 0.51, p = 0.003). Functional predictions revealed increased lipopolysaccharide biosynthesis (ko00540) and reduced butanoate metabolism (ko00650, p < 0.001) in severe disease. Importantly, demographic factors significantly modulated clinical outcomes: cesarean-delivered, formula-fed infants presented the most dysbiotic profiles and experienced 3.2-fold longer hospitalization (95% CI: 1.8–5.6, p < 0.001) than vaginally delivered, breastfed infants did. Conclusions: Collectively, these findings demonstrate that early-life demographic factors potentially shape the gut microbiome composition and function, may influence RVGE severity and recovery trajectories, thus providing candidate biomarkers for risk stratification and identifying targets for microbiota-based interventions.