New rules brought in for the 2016-17 campaign mean managers are allowed to make one more change in extra-time if they have already made three previous swaps.
The law came into effect from the quarter-final stage of this season’s competition, but was not put into practice until a last-four encounter at Wembley.
Pep Guardiola had already replaced David Silva in normal time, with the Spanish playmaker forced off early through injury.
He then shuffled his pack further in extra-time, with Sergio Aguero and Fernandinho making way for Fabian Delph and Fernando.
City were, however, to then fall behind to an Alexis Sanchez effort, with the clock ticking as they trailed 2-1.
As a result, Guardiola opted to throw on Nigeria international striker Iheanacho in the hope of finding a late leveller.
The move did not pay off, as City came up short against the Gunners, but it did write a new piece of English football history.
Ayr United had previously become the first side in Britain to make such a change, in a Scottish Cup clash with Queen's Park in January.