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Southern blot was invented in 1973 but it was not published until 1975. The third innovation is blotting-through methods which was developed by Frederick Sanger, when he transferred RNA molecules to DEAE paper. The second innovation is the gel electrophoresis that based on separation of mixtures of DNA, RNA, or proteins according to molecular size, which was also developed at Johns Hopkins University by Daniel Nathans and Kathleen Danna in 1971. Kenneth and Noreen Murray introduced this technique as Southern. Southern invented Southern blot after combining three innovations, the first one is the restriction endonucleases which were developed at Johns Hopkins University by Tom Kelly and Hamilton Smith, those restriction endonucleases are used to cut the DNA at a specific sequence. The names for other blotting methods may follow this convention, by analogy. As the label is eponymous, Southern is capitalized, as is conventional of proper nouns. Other blotting methods (i.e., western blot, northern blot, eastern blot, southwestern blot) that employ similar principles, but using RNA or protein, have later been named for compass directions as a sort of pun from Southern's name. The method is named after the British biologist Edwin Southern, who first published it in 1975. The Southern blotting combines the transfer of electrophoresis-separated DNA fragments to a filter membrane in a process called blotting, and the subsequent fragment detection by probe hybridization.

The tag allows any DNA fragments containing complementary sequences with the DNA probe sequence to be visualized within the Southern blot. The DNA fragments are transferred out of the gel or matrix onto a solid membrane, which is then exposed to a DNA probe labeled with a radioactive, fluorescent, or chemical tag. Briefly, purified DNA from a biological sample (such as blood or tissue) is digested with restriction enzymes, and the resulting DNA fragments are separated by using an electric current to move them through a sieve-like gel or matrix, which allows smaller fragments to move faster than larger fragments. This method is used in molecular biology. Southern blot is a method used for detection and quantification of a specific DNA sequence in DNA samples.