Background: Malignant neoplasms are the second leading cause of mortality in the United States. Among the cancer sites, leukemia is the seventh most common cause of deaths. It accounts for 3.2% of all new cases of cancer and 3.9% of all cancer deaths. The Mortality-to-Incidence Ratio (MIR) has previously been applied as a measure to examine health disparities and outcomes of cancer therapy. In this study, we aim to analyze leukemia incidence, mortality, and trends of MIR for gender and race over the previous two decades. Methods: We conducted a retrospective population-based study using Cancer Statistics from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research system (CDC WONDER). Subjects with leukemia as the cancer site were selected. Age-adjusted mortality and age-adjusted incidence rates for race and gender were obtained and reported over 100,000 people. Negative binomial regression analysis using age-adjusted rates was subsequently used to analyze mortality, incidence, and trends of MIR. Results: 448,893 deaths were reported to be associated with leukemia between 1999 and 2018, of which males accounted for 56.85%. A total of 894,726 incident cases of leukemia were recorded during the same period. Males had a higher age-adjusted mortality rate than females (9.3 vs 5.2, OR: 1.70 [1.48-1.95]). Compared to Native Americans, African Americans and White cohorts had substantially higher age-adjusted mortality rates (3.5, 6.0, 7.2, OR: reference, 1.74, 2.05), whereas Asians had a non-significantly higher rate (3.8, OR: 1.09 [0.87-1.36]). In males, incidence rates were significantly higher (17.9, OR: 1.61 [1.58-1.64]). Against White population, Asian and African American race had a significantly lower age-adjusted incidence rate (14.4, 7.9, 10.6, OR: reference, 0.60, 0.79), while Native American race had a significantly higher rate (8.2, OR: 1.15 [1.06-1.24]. The mortality-to-incidence ratio has decreased significantly over time in both male and female populations (22.82% and 27.62%, respectively), as well as in African American and White cohorts (24.36% and 23.24%, respectively). Conclusions: Over the last 20 years, the mortality-to-incidence rate ratio significantly declined, possibly suggesting the effectiveness of cancer treatment outcomes in the United States. Yet, the reduction in mortality was not observed in all races. More efforts and further research are needed to guide the policy change.