The 2021–22 National League 2 South was the twelfth and final season (34th overall) of the fourth tier (south) of the English domestic rugby union competitions since the professionalised format of the second division was introduced.
The three teams relegated from National League 2 South the previous season were Sutton & Epsom (London & South East Premier), and Bournemouth and Old Redcliffians (both South-West Premier).
The promoted teams were Barnstaple (champions of South West Premier), while Rochford Hundred and Guernsey Raiders come up as champions and runner-up of London & South East Premier.
The Rugby Football Union restructured the leagues after the 2021–22 season and National 2 South was discontinued.
Barnes, Bury St. Edmunds, Canterbury, Guernsey Raiders, Henley Hawks, Old Albanian, Rochford Hundred, Westcliff and Worthing Raiders were transferred to the newly created National League 2 East while Barnstaple, Clifton, Dings Crusaders, Hinckley, Leicester Lions and Redruth were transferred to another new level four league, National League 2 West.