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<h4>Background</h4>Although rare, small intestine cancer is on the rise in the developed world. We aimed to investigate the incidence trends of small intestine cancer by sex, race/ethnicity, age, and histological subgroups in the United States (US) over 2000-2020. Also, we evaluated the COVID-19 impacts on the incidence trends of this cancer.<h4>Methods</h4>Data were collected from the Surveillance, Epidemiology, and End Results 22 database. Both the average annual percent change (AAPC) and age-standardized incidence rates (ASIRs) were determined. The findings were expressed as counts and incidence rates adjusted for age per 100,000 people with 95% confidence intervals (CIs).<h4>Results</h4>A total of 67,815 cases of small intestine cancer across all age groups were reported in the US between 2000 and 2019. Neuroendocrine carcinoma was the most often reported subtype (54.26%). The age group of 55 to 69 years (38.08%), men (53.10%), and Non-Hispanic Whites (69.07%) accounted for the majority of cases. Over 2000-2019, the ASIRs for small intestine cancer among men and women were 2.61 (95% CI: 2.59-2.64) and 1.92 (95% CI: 1.89-1.94) per 100,000, indicating a significant increase of 2.01% and 2.12%, respectively. Non-Hispanic Black men had the highest ASIR (4.25 per 100,000). Also, those aged 80-84 age group had the highest ASIR. During COVID-19, the ASIR of small intestine cancer decreased by 8.94% (5.06-12.81%).<h4>Conclusions</h4>Small intestine cancer incidence raised in all sexes and ethnicities. Following COVID-19, reported cases declined, possibly due to pandemic-related diagnostic challenges. The impact of underdiagnosis on patient survival needs further investigations.