The animal charity received reports the young feline was hit by several cars after it was thrown onto the eastbound A64 near York.
Witnesses told the charity it was thrown from a dark blue Ford Focus onto the side of the carriageway heading towards Scarborough at 4.50pm on Thursday. The driver appeared to be a white man in his sixties or seventies.
RSPCA inspector Tom Hutton said: “This would have been a very upsetting incident.
"The roads were busy at the time and so we are urging anyone who witnessed this to contact us.”
It is unclear if the kitten survived, as it has not yet been found.
Members of the public who may have any information related to the incident have been asked to contact the RSPCA on 0300 123 8018 or the police.
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