The Yusufzai or Yousafzai (Pashto: یوسفزی, pronounced [jusəpˈzai]¹), also referred to as the Esapzai (ايسپزی, pronounced [iːsəpˈzai]), or Yusufzai Afghans historically, are one of the largest tribes of Pashtuns. They are natively based in the northern part of Khyber Pakhtunkhwa (Malakand, Dir, Swat, Shangla, Buner, Swabi, Mardan, Bajaur, Peshawar, Tor Ghar), to which they migrated from Kabul during the 16th century, but they are also present in parts of Afghanistan, including Kunar, Kabul, Kandahar and Farah. Outside of these countries, they can be found in Ghoriwala District Bannu (Mughal Khel), Balochistan Sibi (Akazai), Chagai (Hassanzai) and Rohilkandh.

Most of the Yusufzai speak a northern variety of Pashto and some southern variety of Pashto (as in case of Mughal Khel) and Afghan dialect Persian.

According to some scholars, including philologist J.W. McCrindle, the name Yūsəpzay or Īsəpzay is derived from the tribal names of Aspasioi and Assakenoi – the ancient inhabitants of the Kunar Valley and the Swat Valley who offered resistance when Alexander invaded their land in 327–326 BCE. According to historian R.C. Majumdar, the Assakenoi were either allied to or a branch of the larger Aspasioi, and both of these ancient tribal names were probably derived from the word Aśvaka, which literally means "horsemen", "horse breeders", or "cavalrymen" (from aśva or aspa, the Sanskrit and Avestan words for "horse").

McCrindle said "The name of the Aśvaka indicates that their country was renowned in primitive times, as it is at the present day, for its superior breed of horses. The fact that the Greeks translated their name into "Hippasioi" (from ἵππος, a horse) shows that they must have been aware of its etymological signification."

The name of the Aśvakan or Assakan is also the origin of the ethnonym Afghān, which has been historically used for all Pashtuns.

The 1595 Mughal account Ain-i-Akbari said there was a tradition of Israelite descent among Pashtuns.

During the early modern period, the Yusufzai tribe of Afghans was first explicitly mentioned in Baburnama by Babur, a Timurid ruler from Fergana (in present-day Uzbekistan) who captured Kabul in 1504. On 21 January 1519, two weeks after his Bajaur massacre, Babur wrote: "On Friday we marched for Sawad (Swat), with the intention of attacking the Yusufzai Afghans, and dismounted in between the water of Panjkora and the united waters of Chandāwal (Jandul) and Bajaur. Shah Mansur Yusufzai had brought a few well-flavoured and quite intoxicating confections."

Due to the military and strategic strength of the Yousafzai, Babur needed security from their location in the hills that threatened his empire and did not allow for a safe expansion to India. As part of a treaty with Yusufzai Afghans to have family ties, Babur married Bibi Mubarika, daughter of Yusufzai chief Shah Mansur on 30 January 1519 for mutual security after failing to subdue the tribe. Shah Mansur had favoured peace while the faction of Malik Ahmad Khan was against any forging of close ties. Bibi Mubarika played an important role in the establishment of friendly relations of Yusufzai Pashtun chiefs with Babur, who later founded the Mughal Empire after defeating Pashtun Sultan Ibrahim Lodi at the First Battle of Panipat in 1526. One of Mubarika's brothers, Mir Jamal Yusufzai, accompanied Babur to India in 1525 and later held high posts under Mughal Emperors Humayun and Akbar. Although suspicions existed on both sides and the Yusufzai had never paid taxes or tributes to Babur or any other Mughal Emperor.