OBJECTIVE@#To study the clinical effect of vitamin D (VitD) combined with the Early Start Denver Model (ESDM) in the treatment of autism spectrum disorder (ASD) in toddlers.@*METHODS@#A total of 102 toddlers with ASD, aged 1 to 3 years, were enrolled. According to the wishes of their parents, they were divided into conventional rehabilitation, ESDM and ESDM+VitD groups. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used evaluate behavior problems before treatment and after 3 months of treatment.@*RESULTS@#The conventional rehabilitation group had significant reductions in the total score and the scores on somatic movement and self-care subscales of the ABC scale after 3 months of treatment (P<0.05). After 3 months of treatment, the ESDM group had significant reductions in the total score and the scores on somatic movement, self-care, social interaction and language subscales of the ABC scale (P<0.05), as well as a significant reduction in the total score of the CARS (P<0.05). After 3 months of treatment, the ESDM+VitD group had a significant increase in the level of 25(OH)D and significant reductions in the total score and the scores on self-care, sensation, social interaction and language subscales of the ABC scale (P<0.05), as well as a significant reduction in the total score of the CARS (P<0.05). The ESDM group had a significantly greater reduction in the score on social interaction subscale than the conventional rehabilitation group (P<0.05). The ESDM+VitD group had a significantly greater reduction in the score on social interaction subscale than the other two groups (P<0.05).@*CONCLUSIONS@#ESDM can effectively improve the clinical symptoms of toddlers with ASD, with a significantly better clinical effect in improving social interaction and somatic movement than conventional rehabilitation. ESDM combined with VitD has a significantly better clinical effect in improving social communication skills and may be one of the best strategies for improving the clinical symptoms of toddlers with ASD.