Land borders include the districts of San Miguel to the west and Sampaloc to the north; and to the northeast is Quezon City.

The Tuason family are the landlords of Santa Mesa during the Spanish colonial period offered an obra pía ("pious work"), and provided social services to the people Doña Albina Tuason also donated the Land where the Church is located even right at this modern days.

[citation needed] Santa Mesa was situated in the alluvial deposits at the confluence of Pasig and San Juan Rivers.

In late 2003, the National Historical Commission of the Philippines had determined that the conflict did not happen on San Juan Bridge, but at the juncture of Sociego and Silencio Streets.

[4] In 1911, Santa Mesa became a separate religious district out of Sampaloc when the first and oldest parish in the Philippines in honor of its titular patron, the Sacred Heart of Jesus, was established.

The neighborhood was composed of wealthy and aristocratic Spanish and Filipino families who built summer houses, examples of which are the Sociego Mansion, formerly home of the Tuason family, and the Carriedo Mansion (currently known as the Antique House in Pureza), formerly home of Governor General Francisco Carriedo y Peredo who spearheaded the clean water system of the City of Manila.

The abundance of these trees started a perfume industry in Santa Mesa—flowers were harvested, pressed and the oil were exported in great quantities to perfumeries in France.

It is bounded to the west by Lacson Avenue separating it from San Miguel; by Ramon Magsaysay Boulevard to the north bordering it from Sampaloc.