Mark, Samantha's boyfriend, told TMZ the pair were driving near a toll booth when they had a "paparazzi confrontation".
TMZ reports that Samantha, who has multiple sclerosis, "hit the windshield and fell to the floor mat", and was taken to the hospital where she's receiving treatment.
She and her brother, Thomas Markle Jr, have not been invited to the royal wedding.
Meghan Markle's Half Sister Hospitalized with Possible Broken Ankle After Paparazzi Run
This comes as Markle's half-sister launched a scathing attack on the USA actress just days before the Royal Wedding. The boyfriend claims he drove Samantha to the E.R. where she's being checked out for a possible broken ankle and fractured knee.
"She's not qualified to suggest that I don't under any law in this country".
"If its about my life or my father's there is something in this country called freedom of speech".More news: USA move on Iran threatens €143m Irish export trade
Samantha has claimed she only lost contact with Meghan a year ago. 'Meghan's way out of her league to tell me I can't speak'.
'This is not Great Britain. "I searched the world for something that I thought was really sentimental and I'll like to give it to her in person, but if not, I will certainly send it". "I'm not going to take it", she continued.More news: 'Serial' Heads to HBO for 'The Case Against Adnan Syed'
The Sun also reported that Samantha Markle had "slammed claims" that Kensington Palace was assisting their father financially during his hospital stay. He is trying to make peace after everything that has happened. There's no bigger media vulture with this wedding than you, is there? But her mother, Doria Ragland, will be there!
The ex-model has been criticised for making a string of waspish comments about Meghan since her engagement to Prince Harry. Her estranged half-sister, Samantha Grant, said she would not stop talking to the media before the royal wedding.More news: May 21: Virginia Voter Registration Deadline