The 2005–06 season was the 91st in the history of the Isthmian League, which is an English football competition featuring semi-professional and amateur clubs from London, East and South East England.
Braintree Town won the division and were promoted to the Conference South along with play-off winners Fisher Athletic, who earned a second consecutive promotion.
Maldon Town, Windsor & Eton and Redbridge were relegated, while Hendon were initially relegated too as the worst 19th-placed club among the seventh level leagues, but were reprieved after Canvey Island resigned from the Conference.
Following this season, clubs remaining in the division were distributed between local ninth tier leagues.
The ten clubs to have made it through the Second round were entered into the Third round draw with the twenty-two Premier Division clubs, making thirty-two teams.