Mildred was the only child of Nicholas Meriwether (~1714–1739) and his wife Mildred Thornton (1721–1779). Nicholas was the son of William Meriwether who tried to establish the town of Newcastle. After the death of Nicholas, her mother Mildred (Thornton) Meriwether married the notable explorer Dr. Thomas Walker and had at least 9 additional children.

In 1753, when she was about 14 years old, Mildred married John Syme II. John was the son of John Syme and Sarah Winston and became the half brother of Patrick Henry, the noted Revolutionary War firebrand when his widowed mother Sarah married John Henry.

John and Mildred were the parents of four children: Mildred (~1754–1779), John III (~1756–1793), Nicholas Meriwether (~1759–1808 or 1812) and Sarah Syme (1760–1814).

Sometime after the marriage John moved his family to Newcastle or Mildred's nearby plantation that she had inherited from her father, Nicholas, and grandfather, William.

Mildred died in the early 1760s but John remarried (Sarah Hoops) and continued to live and work at Newcastle until he eventually built "Rocky Mills" and moved there about 1782

Mildred is mentioned in the will of Nicholas Meriwether II but her relationship is not specified.

"Item. I give and bequeath unto Mildred Meriwether Daughter of Nicholas Meriwether deceased one Negro Girl of about her own age to be Delivered at the Division of my slaves hereinafter mentioned to her and her Heirs forEver."

Research has proven that her father was "Nicholas the Younger", son of William Meriwether, the son of Nicholas II, and she was therefore a great-granddaughter of Nicholas II. Many early Meriwether genealogies mistakenly have her as daughter of Nicholas Meriwether III, son of Nicholas II; Nicholas III died before 1721, unmarried.
∼TMSI [335]: M121 GG-Granddaughter of Nicholas Meriwether & Elizabeth (?) Meriwether Browne.

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References:
"Which Nicholas Married Mildred Thornton?", Maury W. Kendall, Meriwether Connections, vol. 14 number 3, Jul-Sep 1995, http://tmsi.j777.org/article_archive/which_nicholas_married_mild.html

"The Meriwether Family in America, Volume I: The Colonists.", The Meriwether Society, 2017.

"John Syme's Rocky Mills Mansion in Hanover County, Virginia", V. Cabell Flanagan, The Patrick Henry Memorial Foundation, 2004.