Background and Objectives: Sepsis and septic shock remain leading causes of morbidity and mortality in intensive care settings worldwide. While substantial epidemiological data exist from Western countries, the clinical profile of sepsis in regions with exceptionally high diabetes prevalence remains inadequately characterized. Saudi Arabia, with one of the highest diabetes mellitus prevalence rates globally, may exhibit distinct sepsis epidemiology, infection patterns, and outcomes. This study aimed to characterize the clinical profiles, antimicrobial management, and outcomes of sepsis and septic shock in a tertiary intensive care unit (ICU) in the Aseer region of southwestern Saudi Arabia. Materials and Methods: A retrospective observational study was conducted including 263 adults meeting Sepsis-3 criteria (232 sepsis, 31 septic shock) admitted to a tertiary ICU between January 2020 and December 2024. Demographics, comorbidities, laboratory parameters, microbiological data, antibiotic timing, interventions, and in-hospital mortality were analyzed. Logistic regression identified independent mortality predictors. This study adhered to the STROBE reporting guidelines. Results: The median age was 73 years with male predominance (58.4%). Diabetes mellitus (71.5%) and hypertension (65.8%) were highly prevalent. Urinary tract infections (UTIs) predominated (79.8%), with Escherichia coli as the most common pathogen (26.2%). The median time to antibiotic administration was 1.8 h; piperacillin–tazobactam was the most frequent empiric regimen (43.7%). Septic shock patients exhibited higher creatinine (1.65 vs. 1.08 mg/dL, p = 0.026) and lower platelets (194 vs. 271 × 10³/μL, p = 0.030). Mortality was 38.7% in septic shock versus 8.2% in sepsis (p < 0.001). Multivariate analysis confirmed septic shock (aOR: 5.23; 95% CI: 1.89–14.48) and mechanical ventilation (aOR: 15.42; 95% CI: 5.67–41.95) as independent mortality predictors. Conclusions: High diabetes prevalence shapes regional sepsis epidemiology with UTI predominance. Early antibiotic administration and recognition of septic shock remain critical for improving outcomes in this population.