De Villiers, who last played in a Test more than 19 months ago, was sorely missed in the batting order as the Proteas suffered a 3-1 series defeat in England, their first Test series loss in the UK since 1998.
The now 33-year-old De Villiers decided in January this year to take a sabbatical from the longest format in order to preserve his body for limited-overs cricket.
It is expected that De Villiers, who averages more than 50 with the bat after 106 Tests, will call time on his career in the Test whites and Du Plessis said the Proteas must find a replacement.
Du Plessis told reporters after the Proteas' 177-run loss at Old Trafford: "I would love AB to play - we all know how good he is and we missed him, but we've spent too much time talking about when he is going to come back.
"The hope of him coming back is something we need to move past, we need to find someone else to fulfill that role.
"If AB comes back it's a huge bonus but I don't expect him to come back into the Test team."
The batting has looked vulnerable over the last year but was exposed in English conditions as the visitors suffered one batting collapse after another.
Three players were tried in De Villiers' number four position in the order. JP Duminy was dropped after the first Test at Lord's, wicketkeeper Quinton de Kock batted at four in the next two Tests while Temba Bavuma was given the responsibility in the final game of the series.
"We didn't come here planning for JP to be dropped, we were hoping that he could bowl and play those x-factor innings," said Du Plessis.
The Proteas' next Test series will be a two-match affair against Bangladesh at home before they play India and Australia, also on home soil.