Background and Objective: Obtaining reliable and up-to-date information on mortality causes is essential for planning and implementation of effective preventive interventions. We present here an analysis of the leading causes of death in the US in 2022. Material and Methods: We conducted an electronic search of the US Centers for Control and Prevention (CDC) Web-based Injury Statistics Query and Reporting System (WISQARS) to obtain information on the leading causes of death in the US for the most recent searchable year (2022), stratified by age and sex. Results: Overall, heart disease was the leading cause of death (26.2% of all deaths), followed by malignant neoplasms (22.7%), unintentional injuries (8.5%) and coronavirus disease 2019 (COVID-19; 6.9%). Although heart disease and malignant neoplasms remained the leading causes of death in both sexes, unintentional injuries were the third cause for men (10.5%), while strokes were the third cause in women (7.5%). COVID-19 remained the fourth most common cause of death in both sexes (7.1% in men and 6.8% in women). The ten most common causes of death showed an increasing mortality tendency in parallel with the aging of population, with similar trends for both sexes. The only exception was unintentional injury, which was the most common cause of death in both sexes between the ages of 15 and 44 years, then reached a plateau, for increasing again in people aged 65 years or older. Conclusions: Greater efforts should be put into prevention and education, as heart disease, cancer and even unintentional injuries are preventable diseases.