Background: The primary goal of our study is to assess the national US prevalence of autism spectrum disorder (ASD), along with its socio-demographic characteristics, severity, and co-occurring medical and psychiatric disorders, using data from the 2020–2021 National Survey of Children’s Health (NSCH). Methods: We analyzed 2020–2021 NSCH data to estimate the prevalence of ever-diagnosed and current ASD among 79,182 children and adolescents (3–17 years). Univariate and multivariate regression models were used to examine associations between medical and psychiatric co-morbidities, socio-demographic factors, and ASD severity. Results: Adolescents (11–17 years) and males were more likely to have ASD, with males comprising 78.7% of the ASD group. The mean age of the sample was 10.1 ± 4.6 years, and 3.2% had an ASD diagnosis. Children from lower-income households and those with caregivers who completed only a high school education were more likely to have ASD. Nearly 96.4% of children with ASD had at least one co-morbid condition. The most common neuropsychiatric co-morbidities were developmental delay (64%), behavioral and conduct problems (57.8%), and anxiety disorder (45.7%), while the most common medical conditions were allergies (32.4%), genetic disorders (26.2%), and asthma (12.6%). Gender disparities in ASD presentation were evident that females with ASD were more likely to experience vision problems, cerebral palsy, epilepsy, depression, and intellectual disability but had lower odds of ADHD and anxiety problems. Greater ASD severity was linked to higher odds of intellectual disability (OR: 5.8, p < 0.001), developmental delay (OR: 5.0, p < 0.001), epilepsy, Down syndrome (OR: 3.4, p < 0.001), vision problems (OR: 2.5, p < 0.001), and genetic disorders (OR: 2.3, p < 0.001). Conclusions: This study provides updated prevalence estimates of ASD and highlights the high burden of co-morbidities, emphasizing the need for comprehensive, multidisciplinary approaches in ASD management. Additionally, our findings emphasize gender differences in ASD presentation, which should be considered in future research and clinical practice to ensure more tailored diagnostic and intervention strategies.