The England international came off the bench to help Brendan Rodgers’ side move into the top-four, heading home unmarked after a smart ball across the box from Cengiz Under.
Vardy being left alone in the penalty area with so much space was already likely to be costly.
But Gabriel Magalhaes had spotted the danger in the buildup and attempted to make Mustafi – who came off the bench to replace the injured David Luiz – aware of the problem.
He was seen pointing repeatedly at the area that needed covering but Mustafi, despite looking at his centre-back partner, did not adjust his position.
Moments later, the ball was lofted over the Germany international and an unmarked Vardy headed home.
Despite the defensive error on Mustafi’s part, his manager Mikel Arteta was more frustrated with the lack of cutting edge, with Alexandre Lacazette particularly guilty of missing a glorious opportunity.
‘It’s very difficult to create chances against ten men behind the ball,’ said Arteta.
‘In those spaces we saw what they did against Manchester City. I was expecting them to do it but we had open situations where we should have finished better.
‘It comes down to two or three chances that you are going to have. When you have those moments you have to take them and not make mistakes at the back.’
‘I think the first half we had the game in our hands,’ said Arteta.
‘We create enough chances to go in front. We score a goal that I don’t know how the hell it was disallowed.
‘Second half it was a case of being patient and waiting for the right moment against a team that wanted to defend really deep, that didn’t have any shots on targets and were just waiting for a mistake to hit you on the break.
‘The moment that we had a minimal mistake with no pressure on the ball trying to step in they caught us with the space in the back and we lost the game.’