The Treaty of Paris in 1898 marked the formal acquisition of the Philippines by the United States, ushering in an era of American influence and governance. Despite initial Filipino resistance, American military might prevailed, leading to President William McKinley's declaration of intentions to "educate, uplift, civilize, and Christianize" the Filipino populace under the guise of Benevolent Assimilation. This policy, viewed as a departure from traditional colonialism, aimed to prepare the Philippines for eventual independence, distinguishing it from the practices of previous colonial powers.

The period saw the disestablishment of the Catholic Church as the state religion, opening doors for Protestant missionaries. Backlash against Catholicism and a favorable view of Protestantism from Americans fueled missionary efforts. In 1901, the Evangelical Union was founded to unite Protestant denominations and foster local Protestant movements.

Significant changes ensued in the social sphere, including the first national census in 1903, revealing a population increase attributed to improved health, sanitation, food production, infrastructure, and education. The development of the public school system, highlighted by the establishment of Manila High School in 1906, fostered a generation of notable Filipino statesmen and political figures. Additionally, the Jones Law laid the groundwork for an autonomous government capable of national elections, marking a pivotal step towards Philippine self-governance.

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During the American period, Intramuros retained its significance as a center of both governance and military operations. It housed crucial government bodies like the House of Representatives in the Ayuntamiento and the Philippine Senate in the Intendencia, with eminent political figures such as Sergio Osmeña and Manuel L. Quezon leading these institutions. The area also served as a vital military base for the 31st infantry battalion of the US army, with officers strategically located around General Luna and Padre Burgos Street.

Under American influence, Intramuros saw substantial infrastructure developments managed by the Bureau of Public Buildings. The arrival of architect Daniel Burnham brought forth visionary plans aligned with the City Beautiful Movement, aiming for a modernized Manila while preserving Intramuros' historical essence. Burnham's proposals included transforming the moat into lush green spaces and improving transportation along the Pasig River.

Despite some institutions relocating, Intramuros remained a bustling community with a diverse population, including students, government workers, and informal settlers, leading to the establishment of boarding houses in parts of the district. Its religious importance persisted, evident in the continuous celebration of year-round festivals and the growth of Catholic settlements post-WWII, highlighting Intramuros' enduring cultural and historical significance.