Asfandyar Wali Khan joined the opposition to Ayub Khan as a student activist. In 1975, he was imprisoned and tortured by the government of Zulfiqar Ali Bhutto and convicted as part of the Hyderabad tribunal for 15 years. Released in 1978, he stayed away from electoral politics till 1990..
Asfandyar Wali Khan served as leader of the Pakhtun Student Federation prior to being elected to the provincial Assembly in the 1990 election, while in the 1993 election he was elected to Pakistan's National Assembly. A seat to which he was re-elected to the National Assembly in the 1997 election and served as Parliamentary leader of the ANP and Chairman of the standing committee on inter-provincial co-ordination.
In 1999, he was elected party president for the first time. He was defeated in the 2002 election, in what was a repeat of his father's defeat in 1990, when a tactical alliance was formed by all the anti-ANP groups against him. After his defeat he resigned as President of his party, only to be re-elected unopposed in the subsequent party election. In 2003 he was elected to the Senate as Senator for a 6 year term. He was re-elected to the National Assembly in the parliamentary elections that was held on February 2008, leading his party to power both provincially and nationally, the former for the first time since 1947 and the latter since 1997.
In September 2008, he was elected as Chairman of the standing committee on foreign Affairs.
In 2008 it was reported by Dawn (newspaper) that he made a secret visit to the United States in which he made high level contacts with the U.S
On 3 October 2008, he was targeted by a suicide bomber who attempted to kill him while he was greeting guests during Eid ul-Fitr. Shortly after the attack, Asfandyar Wali Khan left Charsadda in a helicopter sent by the Prime Minister. He has come under severe criticism by certain elements who alleged that he should have stayed after the attack and attended funerals of the deceased, instead of escaping his home. However, this charge has been dismissed by his supporters as concocted by supporters of Taliban. It has been stated that: "Asfandyar Wali Khan has not fled the country. He is away from the country, no doubt, and is busy with personal and party commitments abroad.
Nevertheless, the establishment feels that Asfandyar Wali and the ANP are probably not contributing their bit towards the true national cause; for in the establishment’s opinion ANP is potentially capable of reversing the Talibanization trend in the tribal areas. Even if the establishment’s viewpoint is true, it is the handling of any situation that matters. Anything mishandled is in fact ruined. The problem at hand can only be solved if the establishment acts sensibly enough to recognize the high stakes involved, such as the growing influence of religious extremists in the region and the increasing number of suicide attacks within Pakistan itself.
Asfandyar Wali has a rightful claim when he tries to make the establishment realize that ‘Pakhtuns’ are something to be owned up, as dearly as the people of any other province. He and his party – ‘The Awami National Party’ have an ideology that they hold dear, and it gives them a sense of belonging to what they are.