From 2014, Nüßlein served as deputy chairman of the CDU/CSU parliamentary group, under the leadership of successive chairmen Volker Kauder (2014-2018) and Ralph Brinkhaus (since 2018).

From 2015 until 2016, he was part of a government-appointed commission tasked with recommending how to safeguard the funding of fulfilling Germany's exit from nuclear energy, under the leadership of co-chairs Ole von Beust, Matthias Platzeck and Jürgen Trittin.

[2][3] In the negotiations to form a fourth coalition government under Merkel's leadership following the 2017 federal elections, Nüßlein led the working group on health policy, alongside Hermann Gröhe and Malu Dreyer.

In February 2021, Nüßlein's parliamentary offices were among 13 properties raided in Germany and Liechtenstein as part of a probe into suspected corruption and bribery of elected officials related to the procurement of FFP-2 masks amid the COVID-19 pandemic.

[6] On March 07, 2021 Nüßlein announced that he would not stand in the 2021 federal elections but instead resign from active politics by the end of the parliamentary term.