Miguel Lopez de Legazpi played a crucial role in initiating Spanish contact with the Tagalogs and establishing European presence in Manila. In 1564, Legazpi led an expedition to assess the island's resources, foster trade relations, forge alliances, and report to Spain. Facing hostilities and logistical challenges in Cebu, Legazpi aimed to relocate to Maynila. However, encounters with Raja Sulayman led to tensions and a skirmish with cannon fire, highlighting the complex dynamics of early Spanish-Tagalog interactions during colonial expansion.

In 1571, Miguel Lopez de Legazpi's expedition marked a turning point in Manila's history. On arrival, locals set parts of the city ablaze, prompting negotiations for peace with the Spaniards. This resulted in an agreement where the Tagalogs paid tribute and ceded control of the south bank of the Pasig River to the Spanish. The chosen area, strategically significant, became the site for a fort that laid the foundation for Spanish rule in Manila. Initially constructed with coconut trunks and earthworks at the river's mouth, the fort's beginnings on 16 May 1571, evolved into Fort Santiago, an enduring symbol of Manila's colonial era.

Concurrent with Legazpi's expedition were the inaugural Roman Catholic missionaries, dispatched by various religious orders to propagate the faith among the indigenous populace. Notably, the Augustinians made a lasting imprint within Intramuros, epitomized by San Agustin Church. Its resilience was proven through surviving fires in 1574 and 1583, and its subsequent reconstruction in 1587 under Juan Macias' guidance, symbolizing a shift towards robust Philippine architecture. This architectural progression extended to fortified walls and stone structures, reflecting a comprehensive urban planning approach to withstand adversities while accommodating urban growth.

The Franciscans, arriving in 1578, established hospitals and documented indigenous customs. The Jesuits, arriving in 1581, fortified Manila's defenses and pioneered standardized education, fostering intellectual development and cultural exchange. Their later re-establishment in 1859 catalyzed educational advancements, birthing institutions like Ateneo Municipal de Manila, instrumental in shaping Filipino identity and independence ideals. Lastly, the Dominicans, arriving in 1587, contributed significantly to education with the establishment of the University of Santo Tomas and Colegio de San Juan de Letran, solidifying Intramuros as a hub of knowledge pivotal in fostering national consciousness and resilience against colonial hegemony.