Question How will the landscape of cancer incidences and deaths change in the next 2 decades? Findings In this cross-sectional study, the results estimate that leading cancer incidences and deaths in the US will be notably different in the year 2040 compared with current rankings. Estimates included increases in melanoma incidence, pancreatic cancer deaths, and liver cancer deaths, and decreases in prostate cancer incidence and breast cancer deaths. Meaning These estimates will be important to guide research, health care, and health policy efforts and emphasize the importance of cancer screening, early detection, and prevention. This cross-sectional study examines recent data from the Surveillance, Epidemiology, and End Results Program and US Census to estimate projections for US cancer incidence and deaths to 2040. Importance Coping with the current and future burden of cancer requires an in-depth understanding of trends in cancer incidences and deaths. Estimated projections of cancer incidences and deaths will be important to guide future research funding allocations, health care planning, and health policy efforts. Objective To estimate cancer incidences and deaths in the United States to the year 2040. Design and Setting This cross-sectional study’s estimated projection analysis used population growth projections and current population-based cancer incidence and death rates to calculate the changes in incidences and deaths to the year 2040. Cancer-specific incidences and deaths in the US were estimated for the most common cancer types. Demographic cancer-specific delay-adjusted incidence rates from the Surveillance, Epidemiology, and End Results Program were combined with US Census Bureau population growth projections (2016) and average annual percentage changes in incidence and death rates. Statistical analyses were performed from July 2020 to February 2021. Main Outcomes and Measures Total cancer incidences and deaths to the year 2040. Results This study estimated that the most common cancers in 2040 will be breast (364 000 cases) with melanoma (219 000 cases) becoming the second most common cancer; lung, third (208 000 cases); colorectal remaining fourth (147 000 cases); and prostate cancer dropping to the fourteenth most common cancer (66 000 cases). Lung cancer (63 000 deaths) was estimated to continue as the leading cause of cancer-related death in 2040, with pancreatic cancer (46 000 deaths) and liver and intrahepatic bile duct cancer (41 000 deaths) surpassing colorectal cancer (34 000 deaths) to become the second and third most common causes of cancer-related death, respectively. Breast cancer (30 000 deaths) was estimated to decrease to the fifth most common cause of cancer death. Conclusions and Relevance These findings suggest that there will be marked changes in the landscape of cancer incidence and deaths by 2040.