The predecessor to the district is the Oberamt Heilbronn, which was created in 1803 when the previously Free Imperial City of Heilbronn was incorporated into the Electorate of Württemberg. In 1926, about half of the Oberamt (old district) of Weinsberg was added. In 1938, it was recognized as a district, and in addition to the previous Oberamt, parts of the dissolved Oberämter Neckarsulm, Brackenheim, Marbach and Besigheim were added. The city of Heilbronn was not included into the district. In 1973, the Landkreise (districts) were reorganized, and part of the dissolved districts of Sinsheim, Mosbach, Buchen and Schwäbisch Hall were added. Within the following two years 5 municipalities were incorporated into the city and therefore left the district, which got its current borders in 1975.
The main river in the district is the Neckar, which flows through the district from the south to the north. The western part of the district belongs to the landscape Kraichgau, the east to the Hohenloher Ebene, Kocher-Jagst-Ebene, and the Löwensteiner Berge.