The Blues will head to the League Two side’s Brisbane Road ground on Tuesday, July 19, for a 7pm kick-off.
It will be the Fratton Park side’s first trip back to the O’s since October 2016, when a Christian Burgess header handed the visitors a 1-0 win in the bottom tier.
The game is the fifth to be confirmed by Pompey as they continue to set out their preparations for the 2022-23 season.
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Their pre-season schedule begins with a game at the Hawks on Saturday, July 2, before the Blues visit Gosport Borough 24 hours later.
Danny Cowley & Co will then spend the week commencing Monday, July 4, in Spain, where a yet to be determined game will take place.
A trip to Gillingham awaits on their return on Saturday, July 16, before the Fratton Park outfit head to east London and their friendly against Orient.
A Blues XI will take on Bognor at Nyewood Lane on Wednesday, July 20, while Pompey are yet to confirm the opposition for a friendly pencilled in for Fratton Park on Saturday, July 23 – one week before their 2022-23 League One season kicks off.
Leyton Orient are currently managed by Richie Wellens, who replaced the sacked Kenny Jackett in March.