The Dutchman is yet to oversee a win as Red Devils boss, having lost to Swansea and drawn with Sunderland, but will hope to record a maiden victory over lower-league opposition.
The Dutchman has not made the early impact a fine preseason suggested he might have at Old Trafford, a 2-1 home defeat against Swansea City preceding a lackluster 1-1 draw at Sunderland.
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And Van Gaal will be targeting an improvement in United's passing, which he bemoaned following the draw at Sunderland.
"We were dominating but you need creative passing in the last third and that was also not so good," he said. "We do not want to be dominating without creating chances. Creating chances and making goals is the purpose of a game. We must improve the passing."
Adding to Van Gaal's concerns is a growing injury list. New signings Ander Herrera (ankle) and Luke Shaw (hamstring) are both set to be sidelined for the coming weeks, while United is also without Michael Carrick (ankle) and Jesse Lingard (knee).
It is a similar story in defense, where Chris Smalling was withdrawn against Sunderland because of a groin injury, meaning United was forced to deploy two youngsters - Tyler Blackett and Michael Keane - alongside Phil Jones in a back three.
"It is unusual to have four injuries in midfield. Every club that has that has a problem," Van Gaal said. "That is why I played [Adnan] Januzaj in midfield [as a substitute versus Sunderland]. When you have a lot of injuries like now then you always need players."
However, there may be good news on that front with the potential availability of new signing Marcos Rojo, who missed out against Sunderland having not received a work permit.
United reached the semifinal stage of the competition last season, but was beaten by Sunday's opponents Sunderland.
MK Dons has made an encouraging start to its League One campaign, winning two and drawing one of its first four matches and it will be eager to claim a major scalp in order to progress to the third round.
Defender Lee Hodson (ankle) is set to miss out once again for the home side and it remains to be seen if goalkeeper David Martin (hip) is available to return.