Mbeki would excel in his studies, and in 1954, he attended Lovedale College in Alice, a school founded by missionaries that would educate the country's future leaders. At Lovedale College, Mbeki joined the ANC Youth League and became active in student politics. In his final year of high school, Mbeki joined in a class boycott against the expulsion of another student that would cause him to be expelled. 

In 1961, Mbeki convinced his parents to let him stay in Johannesburg with Duma Nokwe, an influential ANC leader and lawyer. In Johannesburg, Mbeki met Nelson Mandela and many leaders of the ANC for the first time. As a result of the ANC's banning, the party decided that Mbeki should go into exile. This moment is important to note because this even shaped Mbeki by placing him under the care of Oliver Tambo, his future mentor. 

Mbeki would go on a daring escape with a group of comrades disguised as a football team. On their first attempt, the group was sent back after being caught by South African police. On the second attempt, the "football team" made it to Botswana, but the Zimbabwean police caught them and planned to hand them over to the South African authorities. However, a combination of Mbeki's strong arguments and a helpful court clerk saved them from the situation. 

Over the next few decades, Mbeki would be sent to Russia and parts of Africa to receive training and occupy positions that furthered the ANC's goals. In 1970, Mbeki was sent to the Soviet Union to receive political and military training at the Lenin International School in Moscow. After a year in Russia, Mbeki was transferred to Lusaka, Zambia, where he was in talks with the Botswana Government to open ANC offices within the country. 

In 1978, Mbeki was appointed as Oliver Tambo's political secretary and Director of Information. Mbeki essentially became Tambo's right-hand man, and in return, Tambo provided him with protections that made him untouchable. Tambo's protection allowed Mbeki to speak his mind at meetings, even when it angered many factions of the ANC. If it were not for Tambo, Mbeki would be a political outcast because of his regular policy statements without consulting the ANC's higher authorities. 

From the 1980s to the 90s, Mbeki played an essential role in facilitating negotiations between the ANC and the apartheid government. Within this timeframe, he was appointed as the head of the ANC's Department of Information and Publicity and the Department of International Affairs. He wrote op-eds in the New York Times that called out the United States and stated that "Washington even [had] the gall to present a worsening situation as one that [was] improving." He wrote that "We in the African National Congress are therefore left with no alternative but to conclude that the Administration supports apartheid." These articles that he wrote in high-profile newspapers around the world placed Mbeki as a leader in the eventual downfall of apartheid and played a major role in swaying international opinion.

All while holding these positions and climbing the ranks of the ANC, under Tambo's tutelage, Mbeki was able to master his craft of diplomacy and gain supporters. Later on, many of his rivals were strong contenders for president, but some were assassinated and others lacked enough support. Instead of making passionate speeches, Mbeki preferred privately winning over businessmen of all races. Although Nelson Mandela favored another candidate to succeed him, Mbeki had won over the elders of the ANC and thus gained enough support to become the second president of South Africa. By 1993, Mbeki was appointed as the Chairman of the ANC, which led to him becoming the deputy president of the new government.