In the negotiations to form a coalition government following the 2009 federal elections, Maizière led the CDU/CSU delegation in the working group on taxes, national budget, and financial policy; with Hermann Otto Solms of the FDP as joint chairman.

As Interior Minister, Maizière long played down security worries, but he abruptly changed course late in 2010, giving warnings that there were serious indications of terror attacks being prepared in Europe and the United States.

[10] In October 2010, Maizière and Transport Minister Peter Ramsauer banned arrivals of all air cargo from Yemen, after the German authorities had been tipped off by a foreign intelligence service that there were explosives inside a U.S.-bound parcel trans-shipped at Cologne Bonn Airport.

Signaling one of the biggest shake-ups in decades for the German military, in 2011 Maizière unveiled plans to reduce troop numbers, cut bureaucracy, and eliminate duplication inside the Federal Ministry of Defence.

According to the online news edition of the German public television broadcaster ARD, Maizière had said he thought it was unwise to have U.S. commanders direct such attacks from their bases in the United States.

[20] In the negotiations to form a government following the 2013 federal elections, Maizière led the CDU/CSU members in the working group on foreign affairs, defense, and development cooperation; his co-chair from the SPD was Frank-Walter Steinmeier.

The newspaper report, quoting an unnamed NSA official, said the U.S. was particularly interested in the interior minister "because he is a close aide of Merkel, who seeks his advice on many issues and was rumored to be promoting his candidacy for the post of NATO secretary-general.

"[23][24] From the beginning of 2015, the left-wing opposition and media commentators have repeatedly criticized de Maizière over his record as chief of staff in 2005–09, and over what he knew about Germany's Federal Intelligence Service (BND) helping U.S. agencies to spy on European firms such as the defence manufacturer Airbus.

[27] By late 2015, amid the European migrant crisis, de Maizière urged that Europe should set a limit on the number of refugees it takes in and seek out those most clearly entitled to protection.

[28] His critics say he failed to fight for more staff and budget for the Federal Office for Migration and Refugees (BAMF), which falls under his ministry, despite years of warnings from German states that the agency was being overwhelmed with asylum applications.

[30] In 2016, Maizière banned the neo-Nazi group "White Wolves Terror Crew" (WWT) following raids on 15 properties across the country as worries were growing about a rise in right-wing sentiment after the influx of more than a million migrants the previous year.

[33] Ahead of the Christian Democrats' leadership election in 2018, de Maizière publicly endorsed Annegret Kramp-Karrenbauer to succeed Angela Merkel as the party’s chair.

In April 2023, de Maizière was one of the 22 guests at the ceremony in which Angela Merkel was decorated with the Grand Cross of the Order of Merit for special achievement by President Frank-Walter Steinmeier at Schloss Bellevue in Berlin.