The two clubs previously refrained from taking part in the revamped competition but will now join the rest of the Premier League’s top six – Manchester City, Arsenal, Chelsea and Tottenham Hotspur – in participating.
They form part of the 16 invited teams that will join the 48 League One and League Two clubs in the competition, won by Portsmouth last season after they beat Sunderland at Wembley.
Invited teams are selected based on the club’s final league position at the end of the 2018/19 season, with the first 16 with category one Academy status invited to take part.
The round one group stage draw will take place in July, with the first round of fixtures scheduled to take place in the week commencing Monday, September 2.
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Nicky Butt, Manchester United’s head of academy, said: “We are looking forward to being involved in the EFL Trophy next season.
“The competition provides a range of experiences that will act as the ideal platform for the development of our homegrown talent.
“We are always looking to be innovative in order to find the best development path for our young players.
“The opportunity to face senior opponents will benefit them greatly.”
EFL executive chair Debbie Jevans added: “We are delighted to welcome Liverpool and Manchester United U21s to the competition.
“The recent feedback received from clubs and coaches has been very positive with the current format continuing to offer greater revenue for our clubs and competitive first team football for young talent.”