Previously, divorcee Markle, 35, was accused by her half-sister of failing to support her family.
Grant said the Queen's grandson would be "appalled by what she's done".
She also claimed her sister was a "shallow social climber" who would watch programmes showing the Royal Family as a child and had a "soft spot for gingers".
And the mother-of-three, 51, claimed Markle always wanted to be a princess and said she was "narcissistic and selfish".
When Twitter users voiced their support for Markle, Grant hit back saying: "She is the one with the hardened heart. I've always been supportive of her but I won't enable the lies and hypocrisy."
Grant claims that she was dumped by her half-sister in 2008, after she developed MS. Adding that she became a "social climber".
However, Grant has in turn come under fire from her own mother, Roslyn, 71 who says Grant has been dogging Markle for years.
"Everything she has said about her is a lie," Roslyn told The Sun.
Grant, a writer from Florida, said she had brought up the actress for 12 years when she lived in California and declared: "The Royal Family would be appalled by what she's done to her own family.
"The truth would kill her relationship with Prince Harry, he wouldn't want to date her any more because it puts her in a bad public light."