Nazimuddin was born into the aristocratic and wealthy family of the Nawabs of Dhaka, (Dacca), Bengal, on 19 July 1894. His father was Khawaja Nizamuddin and paternal grandfather was Khwaja Fakhruddin. His family hailed from Kashmir and was long settled in Dhaka. He was the maternal grandson of Nawab Bahadur Sir Khwaja Ahsanullah and his mother, Nawabzadi Bilqis Banu, was notable for her own statue. Nazimuddin had a younger brother, Khwaja Shahabuddin, who would later played a vital role in national politics onwards. Being of Kashmiri-Bengali descent, his family spoke both Bengali and Urdu. They were the first cousin of Nawab Khwaja Habibullah son of Nawab Sir Khwaja Salimullah Bahadur who helped laid foundation of Muslim League in 1906.

He was appointed a Companion of the Order of the Indian Empire (CIE) in 1926, and was knighted in 1934 by the King-Emperor, George V, when he was appointed a Knight Commander of the Order of the Indian Empire (KCIE).

After AMU, Nazimuddin went to England and attended Trinity Hall at Cambridge University. He was granted his MA degree in English by Cambridge University. His training in England enabled him to practice law and become a Barrister-at-Law in England. He was knighted in 1934. In 1947–49, Nazimuddin was granted the degree of Doctor of Laws by the vice-chancellor of Dhaka University, Dr. Mahmud Hasan.

Nazimuddin returned to India to join his brother Khwaja Shahbuddin from England, taking interest in civil and public affairs that led him to join the Bengali politics. Both brother joined the Muslim League, and Nazimuddin successfully ran for the municipality election and elected as Chairman of Dhaka Municipality from 1922 until 1929. During this time, he was appointed as Education minister of Bengal. He remained minister of Education till 1934. Later he was appointmented in Viceroy’s Executive Council in 1934 which he served until 1937. In the former capacity he successfully piloted the Compulsory Primary Education Bill; removing disparity that existed in education between the Hindus and the Muslims. As Minister for Agriculture in 1935, he piloted the Agriculture Debtors Bill and the Bengal Rural Development Bill which freed poor Muslim cultivators from the clutches of Hindu moneylenders.

By 1934, the family had estates that covered almost 200,000 acres and was well spread over different districts of Eastern Bengal, together with properties in Shillong, Assam and Kolkata, had an yearly rent of ₤120,000 ($2,736,497.94 in 2017). By 1960s, the majority of estate was relocated from East Pakistan to the different areas of Pakistan, leaving very little of his estate in East.

He participated in regional elections held on 1937 on a Muslim League’s platform but conceded his defeat in favor of Fazlul Haq of Krishak Praja Part (KPP) who was appointed as Prime Minister of Bengal, while assuming his personal role as member of the legislative assembly.

Due to his conservative elite position, he became close associate of Muhammad Ali Jinnah, then-president of the Muslim League, who appointed him as a member of the executive committee to successfully promote Muslim League’ party agenda and program that gained popularity in East Bengal. In 1940–41, Nazimuddin broke away from the coalition led by Premier Fazlul Haq and decided to become a leader of the opposition, leading campaign against Haq’s premiership and primarily focused on Bengali nationalism issues. In 1943, Nazimuddin took over the government from Premier Haq when the latter was dismissed by the governor, John Herbert, amid controversies surrounding in his political campaigns. During this time, Nazimuddin played a crucial political role for the cause for the separate Muslim homeland, Pakistan. About his role, he was asked about the “Pakistan question” by British Governor Richard Casey in 1945 but he showed very little and no interests in discussing the existence of the movement and reportedly quoting: he did not know what Pakistan means and nobody in Muslim League knew.”

From 1945 to 1947, Nazimuddin continued to be served as the chairman of the Muslim League in Bengal, ardently supporting the political cause for Pakistan against the Congress Party. During this time, he had been in brief conflict with Premier Suhrawardy and strongly opposed the United Bengal Movement and led a strong parliamentary opposition in the assembly against Suhrawardy’s administration in April 1947. The conflict between two men mainly existed because Suhrawardy had represented the middle class while Nazimuddin was representing the aristocracy in the assembly.

In 1947, he again contested in the party elections in the Muslim League against Suhrawardy’s platform and securing his nomination as the party chairman for the Muslim League’s East Bengal chapter. His success in the party election eventually led him to the appointed as the first Chief Minister of East Bengal after the Partition of India in 1947 and effectively gained controlled of the Muslim League in the province.

On 14 August of 1947, Governor-General Muhammad Ali Jinnah relinquished the party presidency of the Pakistan Muslim League (PML) to Sir Khawaja Nazimuddin who took over the party of the President of Pakistan Muslim League (PML), due to his party electoral performance. On 1 November 1947, he was appointed as acting Governor-General in the absence of Governor-General Jinnah due to worsening health, and eventually appointed as Governor-General after passing of Muhammad Ali Jinnah, in a crucial support provided by Prime Minister Liaquat Ali Khan on 14 September 1948 to the president Nazimuddin. His oath of office was supervised by Chief Justice Sir Abdul Rashid of the Federal Court of Pakistan, in attendance with Prime Minister Liaquat Ali Khan.

In 1949, Governor-General Nazimuddin established the parliamentary committee, the Basic Principles Committee, on the advice of Prime Minister Ali Khan to underlying basic principles that would lay foundation of Constitution of Pakistan.

In 1950, Nazimuddin released an official policy statement and declared that: “Pakistan would remain incomplete until the whole of Kashmir is liberated.”

After the assassination of Liaqat Ali Khan in 1951, the Muslim League leaders asked Governor-General Nazimuddin to take over the business of the government as well as the party’s presidency as there was no other person found suitable for the post. He appointed Finance Minister Sir Malik Ghulam as Governor-General’s post. Nazimuddin’s government focused towards promoting the political programs aimed towards conservative ideas. During his time in office, a framework was begun for a constitution that would allow Pakistan to become a republic, and end its Dominion status under the English monarchy.

In 1951, Prime Minister Nazimuddin’s government conducted the country’s first nationwide census where it was noted that 57% population of the country was Indian immigrants, mostly residing in Karachi that further complicated the situation in the country. In January 1952, Prime Minister Nazimuddin publicly announced in Dacca’s meeting that: Jinnah had been right: for the sake of Pakistan’s national unity, Urdu must be the official language of Pakistan–East and West. On 21 February 1952, a demonstration in the Bengali Language movement demanding equal and official status to the Bengali language turned bloody, with many fatalities caused by police firings. This demonstration was held when he declared Urdu the National Language of Pakistan, following the previous statement of Muhammad Ali Jinnah that Urdu shall be ‘one and only’ language of Pakistan.

In 1953, a violent religious movement led by far-right Jamaat-e-Islami began to agitate for the removal of the Ahmadi religious minority from power positions, and demanded a declaration of this minority as non-Muslims.

Nazimuddin then requested the Federal Court of Pakistan’s intervention against this action but the Chief Justice, Muh’d Munir did not rule on the legality of the dismissal, but instead forced new elections to be held in 1954. Governor-General Malik Ghulam appointed another Bengali politician, Muhammad Ali Bogra who was then tenuring as the Pakistan ambassador to the United States, as the new prime minister until the new elections to be held in 1954. The dismissal of Sir Khawaja Nazimuddin’s administration, the prime minister, by the governor-general, Malik Ghulam, signalled a troubling trend in political history of the country.

In 1958 he was awarded the highest civilian award titled Nishan-e-Pakistan. Later by the Government of Pakistan, Nazimuddin has been honoured from time to time after his death. In Karachi, the residential areas, Nazimabad and North Nazimabad in suburbs of Karachi, had been named after his name. In Islamabad, there is a road intersection, Nazimuddin Road, that has been named in his honor; while in Dhaka, there is also a road after his namesake.

Sir Khawaja died in 1964, aged 70. He was buried at Mausoleum of three leaders in his hometown of Dhaka.

Even after his dismissal, he and his family remained active in parliamentary politics; his nephew, Khwaja Wasiuddin, an army general serving as GOC-in-C II Corps and later repatriated to Bangladesh in 1974.