Introduction: Cancer and atrial fibrillation (AF) are major public health challenges in the United States, with significant mortality risks and a bidirectional relationship that compounds their burden. Despite substantial documentation of their independent mortality trends, data on concomitant cancer- and AF-related mortality trends remain limited. Methods and Results: We analyzed cancer- and AF-related mortality in the U.S. from 1999 to 2019 using CDC WONDER data, focusing on adults aged ≥25 years. Crude and age-adjusted mortality rates (AAMRs) were calculated, and trends were evaluated using Joinpoint regression. A total of 319,480 deaths were identified, with the AAMR increasing from 4.95 in 1999 to 10.01 in 2019 (AAPC: 3.49%). Males exhibited higher AAMRs than females, while Hispanics demonstrated the greatest increase. Geographic disparities were evident, with the highest AAMRs in Vermont, Minnesota, and Rhode Island and the lowest in Arizona, Georgia, and New Mexico. Conclusion: Cancer- and AF-related mortality has risen significantly over two decades, with notable racial, sex-based, and geographic disparities. These findings underscore the need for targeted interventions to address these inequities and mitigate the growing burden of coexisting cancer and AF.