When the Ostend Manifesto was leaked to the public, the reaction by the nation was very polar. As was to be expected, the South stood in favor of taking Cuba. They were always looking to capture and add new slave states to the nation, thus increasing their influence in the government. In fact, Pierre Soule, the minister to Spain, was known to advocate for the South's right to slaves. Thus, his view that Cuba must be forcefully taken was no surprise.

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While the South's supported the Manifesto, the North was outraged by the leaking of the document. It was seen as an aggressive document, and more importantly, an attempt by the South to swing the balance in government in their favor. The North would not tolerate this attempt to spread the influence of slavery.

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The damage done to President Pierce's administration was irrevocable. The controversy over the Manifesto furthered the splintering of the Democratic Party, and was used to support the formation of the Republican Party. Internationally, the Manifesto was quickly denounced by governments such as Spain, Britain, and France. Due to the backlash that he faced, Pierce abandoned his expansionist plan and made James Buchanan's bid for presidency in 1856 much easier.