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The essay analyzed how the intervention of the United States in the Isthmus of Panama during the 19th century weakened the sovereignty of New Granada —later the Republic of Colombia— and facilitated Panama’s secession in 1903. Its objective was to examine how U.S. political, diplomatic, and military actions undermined Granadine authority and contributed to the separatist process. For this purpose, a historical-analytical methodology was applied, based on a critical review of primary and secondary sources, including international treaties, diplomatic records, and documentation on military and political events of the period. The results showed that U.S. intervention was systematic and sustained, driven by geostrategic and commercial interests within the context of the naval supremacy rivalry between the United States and Great Britain. Episodes such as the “Russell Incident” (1836), The Watermelon Slice Massacre (1856), and more than forty military operations between 1850 and 1902 demonstrated the fragility of New Granada’s sovereignty and the Isthmus’s dependence on U.S. military presence, which encouraged separatist movements that culminated in the secession on November 3, 1903, with Washington’s support. In conclusion, U.S. intervention reshaped the political and military dynamics of the Isthmus, establishing the foundations of American economic and geopolitical hegemony in Panama, and provided a more comprehensive understanding of the formation of the Panamanian state and the lasting effects of geopolitical strategies on national sovereignty and regional stability.