In the course of trying to gain weight before playing the role of Precious Ramotswe, Jill Scott noticed that she had gained seven pounds in one week (an extremely fast and potentially unhealthy weight gain). Concerned, she went to her doctor and discovered the day before she left for Botswana that she was pregnant. After she finished filming the first season, Scott returned to the US and in April 2009, gave birth to her son, Jett Hamilton Roberts.

American Grammy Award-winning singer Jill Scott eventually won the role of Precious Ramotswe over American actresses Oprah Winfrey, Whoopi Goldberg, and Queen Latifah, and also 18 African women considered for the lead

This television show is based on a series of books by Alexander McCall Smith. The first line of the series' first book is, "Mma Ramotswe had a detective agency in Africa, at the foot of the Kgale Hill."). This line is a deliberate literary reference to the opening line of Isak Dinesen's classic memoir about Kenya, Out of Africa (which starts "I had a farm in Africa, at the foot of the Ngong Hills." When Out of Africa (1985) was made into a movie, its director was Sydney Pollack; before his death, Pollack was the executive producer for The No. 1 Ladies' Detective Agency (2008).

The film's producers have signed a 10 year lease for the area at the foot of Kgale Hill, Gaborone, where they have built the fictional shopping center where Precious Ramotswe opens her storefront detective agency.

When cast, both of the lead actresses in this series were a little better-known for their professional singing than for their film or TV acting careers. Jill Scott was most famous as a Grammy-winning R&B and soul singer, though she had also been a spoken-word performer and poet and a stage actress. Anika Noni Rose won a Tony Award for Best Performance by a Featured Actress in a Musical for the Broadway show "Caroline, or Change," and also appeared in singing roles in Dreamgirls (2006) and (after starting The No. 1 Ladies' Detective Agency (2008)) The Princess and the Frog (2009).

The Botswanan currency is the Pula, and during the time the first season was being filmed (mid-2007 to 2008), 1 Pula was worth about 16 U.S. cents.