On 21 October 1774 in Copenhagen, she married Hereditary Prince Frederick of Denmark and Norway, the son of King Frederick V of Denmark and his second wife Juliane Marie of Brunswick-Wolfenbüttel, who was the regent in Denmark between 1772 and 1784.
Sophia Frederica, known as Sofie Frederikke af Mecklenburg-Schwerin in Denmark, was described as jolly, charming and intelligent.