The Terriers put on an honourable performance at Old Trafford and went into the break level, but second half goals from Romelu Lukaku and Alexis Sánchez - his first for the club - ensured a fifth straight loss.
One mistake too many by the Terriers
Huddersfield switched to an impromptu 3-5-2 formation against Liverpool at the John Smith's Stadium in midweek and lined up in a 4-4-2 on Saturday, both different to Wagner's favoured 4-2-3-1 and 4-3-3.
The German head coach confirmed the decision was made especially for the specific opponents and his team's disciplined first half showing at Old Trafford was evidence that it worked at parts of the match.
“We were aware that this is a difficult task in front of us, we wanted to be solid defensively and find a good formation where we frustrated them, and I think it worked.
"We were not able to create our moments in the offence because United were concentrated and focused at avoiding our transitions."
The visitors' hard work was undone in the 55th minute when Jonathan Hogg lost possession in his own half, leading to Lukaku's precise, volleyed opener - another mistake David Wagner rued.
"Unfortunately, we made a mistake and conceded the first one, then we made an individual mistake for the second one.
"It’s frustrating because the players worked so hard but on the other side we have to be honest. These have been difficult fixtures in the last four days with Liverpool and Manchester United.
Home atmosphere the key to survival
Huddersfield Town's home atmosphere has been phenomenal throughout the whole of their debut Premier League campaign and it's one of the things their head coach believes will help avoid the drop.
“What I have seen today, the commitment and working effort, gives me hope for what's in front of us.
"We now have fixtures at home where we have to get this atmosphere and this vibe in the dressing room, in the stands and in the Town that’s all about surviving in the Premier League.
“We now have these fixtures in front of us where we have the chance to pick up points and we will prepare for this.