Washington was inaugurated on April 30, 1789, taking the oath of office at Federal Hall in New York City. Though he wished to serve without a salary, Congress insisted adamantly that he accept it, later providing Washington $25,000 per year to defray costs of the presidency. Washington wrote to James Madison: "As the first of everything in our situation will serve to establish a precedent, it is devoutly wished on my part that these precedents be fixed on true principles." To that end, he preferred the title "Mr. President" over more majestic names proposed by the Senate, including "His Excellency" and "His Highness the President". His executive precedents included the inaugural address, messages to Congress, and the cabinet form of the executive branch.

Washington presided over the establishment of the new federal government, appointing all of the high-ranking officials in the executive and judicial branches, shaping numerous political practices, and establishing the site of the permanent capital of the United States. He supported Alexander Hamilton's economic policies whereby the federal government assumed the debts of the state governments and established the First Bank of the United States, the United States Mint, and the United States Customs Service. Congress passed the Tariff of 1789, the Tariff of 1790, and an excise tax on whiskey to fund the government and, in the case of the tariffs, address the trade imbalance with Britain. Washington personally led federalized soldiers in suppressing the Whiskey Rebellion, which arose in opposition to the administration's taxation policies. He directed the Northwest Indian War, which saw the United States establish control over Native American tribes in the Northwest Territory. In foreign affairs, he assured domestic tranquility and maintained peace with the European powers despite the raging French Revolutionary Wars by issuing the 1793 Proclamation of Neutrality. He also secured two important bilateral treaties, the 1794 Jay Treaty with Great Britain and the 1795 Treaty of San Lorenzo with Spain, both of which fostered trade and helped secure control of the American frontier. To protect American shipping from Barbary pirates and other threats, he re-established the United States Navy with the Naval Act of 1794.

Greatly concerned about the growing partisanship within the government and the detrimental impact political parties could have on the fragile unity of the nation, Washington struggled throughout his eight-year presidency to hold rival factions together. He was, and remains, the only U.S. president never to be formally affiliated with a political party. Despite his efforts, debates over Hamilton's economic policy, the French Revolution, and the Jay Treaty deepened ideological divisions. Those that supported Hamilton formed the Federalist Party, while his opponents coalesced around Secretary of State Thomas Jefferson and formed the Democratic-Republican Party.