Tantawy joined the Alexandria Religious Institute in 1944, and became a member of the faculty of Ausol Aldeen in 1968. In 1972 he became a member of the faculty of Arabic & Islamic Studies at the Islamic University of Libya. In 1980 he moved to Saudi Arabia, where he became chief of the Tafsir branch of the Postgraduate studies branch at the Islamic University of Madinah. He returned to Egypt in 1985, when he became Dean of the Faculty of Ausol Aldeen at the prestigious Alexandria Religious Institute.
In 1986, Tantawy was appointed as Grand Mufti of Egypt on his 58th birthday, 28 October 1986. He held this position for almost ten years, until he was appointed Grand Imam of Al-Azhar Mosque and Grand Sheikh of Al-Azhar University by the President of Egypt, Hosni Mubarak, on 27 March 1996. The Al-Azhar Mosque is one of the most influential and important Sunni Muslim institutions.
Tantawy completed a seven thousand page exegesis of the Qur'an (Al-tafser al-waset). This Tafsir took over ten years to complete. He has also written Bano Israel (The Children of Israel) and Muamlat Al-bank (Bank's Dealings).
In 1989 the Egyptian government's support for Western-style, interest-based banks (long considered anathema by Muslim scholars as usury, or riba) was under siege by the expanding Islamic finance movement. In response to a government request for a ruling, Tantawy (then Grand Mufti of Egypt) issued a fatwa that described some forms of financial interest as tolerable- among them, those paid by government bonds and those on ordinary savings accounts. He declared that charging interest on such bank loans was in fact ribh, or just gaining profit, which was allowable. This eventually allowed the development of a mortgage industry. However, his ruling did not issue as an effectual decree. Tantawy’s rationale was based on an interpretation of the Islamic sources as banning usury (an extreme and manipulative form of interest-taking) but not any and all comparable forms of gain.
During the controversy of the French headscarf ban in schools, he issued a fatwa allowing Muslim girls to take off their headscarves while attending school, using the lesser of two evils principle.
He issued a fatwa which allowed abortion in cases where a woman had become pregnant as a result of rape, though this created controversy and Mufti Ali Gomaa said Tantawy was wrong, and that irrespective of how the life was created, after 120 days an abortion becomes haram,[note 1] forbidden.
Tantawy opposed female circumcision calling it un-Islamic, especially in 1997, when he said "The ulema (theologians) of Islam are unanimous in agreeing that female circumcision has nothing to do with religion" and revealed his own daughter had not been circumcised.
Tantawy took a line against suicide bombings, and unlike his compatriot Yusuf al-Qaradawi, he condemned the use of suicide bombings against Israelis, rejecting the argument that all Israelis were legitimate targets, because at some stage they would all carry a gun. In 2003 he called suicide bombers "enemies of Islam", adding "people of different beliefs should co-operate and not get into senseless conflicts and animosity. Extremism is the enemy of Islam, whereas, jihad is allowed in Islam to defend one's land and to help the oppressed. The difference between jihad in Islam and extremism is like the earth and the sky"
Tantawy wrote a 700-page treatise, Jews in the Qur'an and the Traditions, in which he concluded: "The Qur'an describes the Jews with their own particular degenerate characteristics, i.e., killing the prophets of Allah, corrupting His words by putting them in the wrong places, consuming the people's wealth frivolously, refusing to distance themselves from the evil they do, and other ugly characteristics caused by their deep-rooted lasciviousness ... only a minority of the Jews keep their word ... [But] not all Jews are the same. The good ones become Muslims, the bad ones do not." 
Tantawy took an orthodox stance on women's place in Islam, opposing women as Imams in mixed congregations during Friday prayers (Jumu'ah), saying when a woman "leads men in prayer ... it is not proper for them to look at the woman whose body is in front of them". He also called Haidar Haidar's book, Feast for Seaweed, blasphemous. In 2001 he issued a fatwa banning women from acting as surrogate mothers or from receiving frozen sperm from dead husbands.
In response to the Pope Benedict XVI Islam controversy, he stated "We have no objection if the Pope holds another speech and declares publicly that what the Byzantine emperor had said was wrong. At the same time, the Pope has to apologize frankly and justify what he said".
Speaking after the September 11, 2001 attacks, Tantawy said "It's not courage in any way to kill an innocent person, or to kill thousands of people, including men and women and children." He said that Osama bin Laden's call for a Jihad against the west was "invalid and not binding on Muslims", adding "Killing innocent civilians is a horrific, hideous act that no religion can approve". He said the Qur'an "specifically forbids the kinds of things the Taliban and al-Qaida are guilty of".
In October 2009, Tantawy launched a campaign against the Niqāb (the full-face veil which covers the entire body except for the eyes, increasingly worn by women in Egypt) by personally removing the Niqāb of a teenage girl (after she failed to remove it) at a secondary school affiliated to Al-Azhar University, which he was touring in Cairo's Madinet Nasr suburb, much to the shock of all concerned. He had asked the teenage girl to remove her veil saying: "The Niqāb is a tradition, it has no connection with religion." He then instructed the girl never to wear the Niqāb again and promised to issue a fatwa against its use in schools, saying he was determined to officially ban any person wearing the Niqāb from entering schools dependent on Al-Azhar University.
Tantawy died on the morning of March 10, 2010, at the age of 81, as result of a heart attack during a visit to Riyadh, Saudi Arabia. Tantawy died as he was about to board his return flight to Egypt at Riyadh's King Khaled International Airport. His heart attack came just after he fell whilst boarding the plane. Tantawy had just attended the prize-giving ceremony for the King Faisal International Prize for Service to Islam. He was officially pronounced dead at the Amir Sultan hospital.
Tantawy's death was unexpected and he was described as being in "excellent shape and health" prior to his trip. Egyptian authorities stated that, at his family's request, he would be buried in Medina in Saudi Arabia, which is also the burial place of Muhammad. His burial at the Jannatul Baqee cemetery took place after funeral prayers were held at the Prophet's Mosque. Tantawy's deputy, Mohamed Wasel, is expected to take over his duties until President Mubarak appoints a replacement.
Condolences have been sent to the Egyptian government by several national leaders and scholars. These included Pope Benedict XVI, US President Barack Obama and Secretary of State Hillary Clinton; the Mufti of Singapore, Syed Isa Mohd Semai; the Islamic Development Department of Malaysia (Jakim); King Mohammed VI of Morocco; King Abdullah II of Jordan, President Ali Abdullah Saleh of Yemen and President Ilham Aliyev of Azerbaijan.