Samantha Grant, who shares a father with half-sister Meghan, said she should have invited several family members out of respect.
"At issue is not a matter of closeness as more than 1,000 complete strangers are invited," she tweeted.
"Family is family. I have an uncle I have only seen once by I would never say he is not family because we are not close. Humanitarians move forward with love and kindness especially to family."
Ms Grant, who uses a wheelchair after being diagnosed with multiple sclerosis, later changed her profile picture to a snap of her and Meghan together when they were younger.
She then added: "Smoke and mirrors cannot hide the elephant in the room. Out of respect, tradition and humanitarianism, the #Markles should be invited if 2,000 complete strangers are invited.
"Our uncle who got her the internship, brother, me, best friend of 30 years Nikki Priddy, nephews. Fact."
Though Meghan Markle is still close to her dad Thomas Markle, even though the 73-year-old lives a quiet life near Rosarito in Mexico, however it is still not yet known if he will walk her down the aisle. Meghan's mum Doria is expected to attend after she joined the royal couple at the Invictus Games last year.
Around 1,200 people invited to the wedding are members of the public from a range of backgrounds and ages. Young people who have shown strong leadership and served their communities are among those lucky enough to receive a coveted invitation. 200 guests will be from charities and organisations the couple have a close connection with. Another 100 guests will be from two local schools.