Later in the same year, after the death of Stalin, Mukhitdinov was demoted under pressure from Lavrentiy Beria from the post of the Chairman of the Council of Ministers of Uzbekistan.
Mukhitdinov was reinstated as Chairman of the Council of Ministers of Uzbekistan and was First Secretary of the Uzbek Central Committee of the Communist Party from 1955 to 1957.
However, by the end of the 1950s, Mukhitdinov developed strong disagreements on planning policies with leading party members such as Mikhail Suslov, Anastas Mikoyan, Frol Kozlov, and later with Khrushchev himself.
As a consequence, in 1961 he was demoted from the Presidium and was on the verge of expulsion from the Central Committee, and only his popularity in the native Uzbekistan spared his Party career.
He retained his international activities and in 1968-1977 served as the ambassador to Syria, eventually receiving the Order of Friendship of Peoples.