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Abstract Background: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, with a median age at diagnosis of approximately 70 years. It accounts for nearly 25–30% of all leukemias in the United States. CLL is associated with progressive immune dysfunction, primarily due to disease-related hypogammaglobulinemia and therapy-induced immunosuppression, which together lead to a high susceptibility to infections. Notably, infections are the leading cause of death in up to 50–60% of CLL patients, with sepsis representing a major contributor. Despite this well-established risk, there remains ambiguity of comprehensive, national-level data evaluating long-term trends and geographic variation in sepsis-related mortality among CLL patients. Methods: We utilized the CDC WONDER Multiple Cause of Death database to identify deaths among patients with CLL (ICD-10: C91.1) with sepsis listed as a contributing cause between 1999 and 2022. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population and reported per million. Temporal trends were analyzed using Joinpoint regression to estimate average annual percent change (AAPC). ARIMA models with Box-Cox transformation were applied to forecast mortality through 2030 after validating assumptions using ADF/KPSS stationarity tests and residual diagnostics. Subgroup analyses included breakdowns by sex, race/ethnicity, census region, and urbanicity. Results: A total of 15,397 sepsis-related deaths among CLL patients were recorded between 1999 and 2023. The national AAMR declined from 1.7 per million in 1999 to 1.4 per million in 2022, representing a 17.6% overall decrease. The lowest rate occurred in 2013 (1.3 per million), followed by modest annual fluctuations thereafter. Gender-specific analyses revealed a consistently higher sepsis-related mortality burden among males, who accounted for 9,142 deaths compared to 6,255 among females. The male AAMR declined from 2.1 to 1.7 per million (19.0% decrease), while the female AAMR showed a smaller reduction from 1.3 to 1.1 per million (15.4% decrease), with male mortality remaining significantly higher than that of females throughout the study period. White individuals accounted for the majority of deaths (13,768), with the age-adjusted mortality rate (AAMR) showing a modest decline from 1.7 per million in 1999 to 1.4 per million in 2023. Black or African American individuals had a smaller overall burden (1,444 deaths), with their AAMR decreasing from 1.9 to 1.3 per million over the same period. Among Hispanic or Latino individuals, there were 226 deaths with a slight decline in AAMR from 0.8 in 2008 to 0.7 per million in 2023. Non-Hispanic individuals had the greatest overall mortality (14,932 deaths), and their AAMR fell from 1.7 to 1.3 per million between 1999 and 2023. Marked geographic disparities were observed. The Northeast demonstrated the most substantial decline in AAMR from 2.0 to 1.1 per million (45.0% decrease), accounting for 3,183 deaths. The Midwest and South experienced similar reductions from 1.7 to 1.4 per million (17.6% decrease), with total deaths of 3,633 and 5,501, respectively. The West showed the most stable pattern, maintaining AAMRs around 1.3 per million (3,080 deaths). At the state level, the highest mortality burdens were noted in Kentucky and Mississippi (2.4 per million), followed by Kansas (2.3), while the lowest were observed in Hawaii (0.7), Arizona (0.9), and New Mexico (0.9 per million). ARIMA forecasting suggested continued gradual improvement in sepsis mortality, with projected AAMRs of 1.38 in 2024, 1.35 in 2026, 1.33 in 2028, and 1.31 per million by 2030 (95% CI: 1.18–1.47), indicating stable but ongoing reductions in burden. Conclusion: Sepsis-related mortality in CLL has declined modestly over the past two decades, likely reflecting improvements in infection control and supportive care. However, substantial geographic and demographic disparities persist, signifying the need for region-specific, standardized strategies. Forecasts indicate a continued but slow decline through 2030, reinforcing the urgency of targeted interventions in high-burden populations to ensure more equitable outcomes nationwide.