On 20 October 1947, two months and six days after the independence of Pakistan through the partition of British India, the United States became one of the first nations to establish relations with Pakistan. The relations are a very important factor in the United States government's overall policy in South and Central Asia as well as Eastern Europe.

Since 1948–2016, the United States has provided nearly US$78.3 billion (adjusted to 2016 value of dollar) to Pakistan in grants annually in forms of military aid. Of these aid and funds arrangement, Pakistan was obligated to spend these monetary funds by purchasing American goods, food, and other services. In spite of China being the largest importer and exporter for Pakistan's market, the United States continues to be one of the largest sources of foreign direct investment in Pakistan and is Pakistan's largest export market.The relationship between the two nations, however, has been described as "roller coaster" given by the characterization of close coordination and lows marked by deep bilateral estrangement. From 1979 to 1989, the United States and Pakistan cooperated in the funding and financing of the Afghan Mujahideen who engaged the Soviet Union in the Soviet-Afghan War, with their relations taking a deep dive with the introduction of a unilateral military embargo by the United States over the covert development of nuclear weapons, which Pakistani administrators saw as the only way to defend the nation in light of India's larger military conventional attack in 1990. With sanctions waived in 1994 with Pakistan's willingness to participate with the United States in the wars in Somalia and Bosnia, the United States again suspended aid and imposed sanctions along with India in 1998, only to be lifted once again with the United States engagement in Afghanistan in 2001.

Factors involving in the contingency operations, distrust, and different priorities of both nations in the Afghan War led to serious criticism as both sides began to criticize each other's strategy to achieve common goals in the War on Terror. The American politicians at the U.S. Congress publicly accused Pakistan of harboring of Osama Bin Laden, Afghan Talibans and their "Quetta Shura" while the lawmakers in the Pakistani Parliament leveled serious accusations at the Americans doing very little to control the porous eastern border of Afghanistan, where Pakistan's most-wanted terrorist, Mullah Fazlullah and his organization were believed to be hiding. Furthermore, drone strikes by both nations, a friendly fire incident at Salala, and an incident involving the arrest of a spy in Lahore further complicated relations. These issues sharply soured the public opinion in both nations, with public opinion of each nation ranking the other as one of the least favored countries in 2013.

Despite the troubled events and times, Pakistan continues to occupy an important place in American geopolitical strategy and has been a major non-NATO ally since 2002. Even today, the United States continues to engage with Pakistan in all aspects as the United States is the second-largest supplier of military equipment to Pakistan after China, and is one of Pakistan's largest economic partners in form of direct foreign investment. In addition, Pakistan also hosts one of the largest and most housed embassies of the United States in Islamabad, and the largest consulate-general, in terms of both personnel and facilities, that is located in the city of Karachi.

With Pakistan's Prime Minister visiting the United States on 21 July 2019, Prime Minister Imran Khan and President Donald Trump agreed to "reset" the relationship between the two countries and agreed to strengthen the military relations with President Trump lauded Pakistan's efforts to end the war in Afghanistan due to Pakistan's participation in the Afghan peace process.

As of 2014, 59% of Pakistanis consider the United States to be an enemy, reduced from 74% in 2012. The Pakistanis have the least favorable view of US compared with 39 countries in the world surveyed by Pew. US favorability has ranged between 23 (2005) to 10 (2002) during 1999-2013).There are an estimated 554,202 self-identified Pakistani American living in the United States and about 52,486 Americans residing in Pakistan.