Authorities say Adam Hughes, 24, of Rancho Cucamonga, was watching his girlfriend's children last week when one of them interrupted him, making him angry.
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He allegedly assaulted the girl - 4-year-old Kylee Willis - and then put her to bed.
Hours later he noticed Kylee was unresponsive, with blue fingers and lips. He called his girlfriend, Corrine Blake, and she then called 911.
Paramedics brought Kylee to a local hospital. She remained on life support for several days and then died on March 29.
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After the initial injury, police arrested both Hughes and the girl's mother, Blake, for willful cruelty to a child.
After Kylee died, Hughes was also charged with murder. He is being held without bail. Blake has been released on bail.
"The injuries to the 4-year old were obvious, intentional injuries," said Cindy Bachman, spokesperson for the San Bernardino County Sheriff's Department. "And then upon the investigators interviewing Hughes, he told them that the child - who had Down Syndrome - had interrupted him. He was busy, she had interrupted him and he got angry at her."
Another child at the home, an 18-month-old boy, was taken into custody by county Children and Family Services.