She was born on December 12, 1982 in Bến Tre province located in the Mekong Delta of Southern Vietnam with the given birth name, Mai Thị Hậu. Raised in a poor Roman Catholic household, she got her start in gospel music singing for the local church. Throughout her teenage years, she entered various talent competitions and sang for weddings and parties to earn money to pay for her school books. After high school, she enrolled at Cao Đẳng Sư Phạm Mẫu Giáo Trung Ương 3 University in Ho Chi Minh City. During her sophomore year in college, she competed in the national television talent show, Tiếng Hát Truyền Hình, and won critical praise from judges for her interpretations of Vietnamese folk songs, Khúc Hát Người Đi Khai Hoang (written by Lư Nhất Vũ and Lê Giang) and Đau Xót Lý Chim Quyên (written by Vũ Đức Sao Biển). After graduating from college, she juggled two careers, a school teacher by day and a recording artist for various record labels in Vietnam such as Saigon Audio, Hãng Phim Trẻ and Phương Nam Films. As a recording artist in Vietnam, she was then billed under the name, Mai Hậu.
After resettling in the United States, she was introduced by a mutual friend to Tô Văn Lai, the owner of Thúy Nga, the most prolific overseas Vietnamese music production label. After signing with the label, she changed her professional stage name to Mai Thiên Vân. In 2007, she made her debut appearance on volume 90 of Thúy Nga's popular live show video series, Paris By Night, in a duet performance of the song, Nước Non Ngàn Dặm Ra Đi (written by Phạm Duy), together with singer Quang Lê which became a huge hit with viewer audiences. That same year, Thúy Nga released Mai Thiên Vân's debut solo studio album, Hương Lòng Dâng Mẹ. Mai Thiên Vân has since recorded 7 more well-received solo studio albums released under the Thúy Nga label which include Thương Hoài Ngàn Năm (2008), Nếu Anh Đừng Hẹn (2009), Cung Chúc Trinh Vương (2009), Hát Để Tặng Anh (2010), Thánh Tâm Chúa (2011), Bao Giờ Em Lấy Chồng (2012) and Ave Maria Trăng Từ Bi (2015) along with several duet studio albums with Quang Lê, Trường Vũ and Tuấn Quỳnh. Mai Thiên Vân has also recorded many duet songs with various other artists including Thế Sơn, Mai Quốc Huy, Đình Bảo, Duy Trường, Thanh Tuyền, Mạnh Quỳnh, Đan Nguyên, Hoàng Oanh, Phi Nhung, Hương Lan and Thái Châu. She has appeared on more than 40 volumes of the popular Paris By Night series. In 2017, Thúy Nga produced and released a DVD, Liveshow Nhật Ký Đời Tôi, starring Mai Thiên Vân with special guest appearances by Trường Vũ, Mạnh Quỳnh, Đan Nguyên, Jenny Đan Anh, Lena Phương Vy, Hạ Vy and Minh Tuyết.
