The union of the crowns of Spain and Portugal in 1580 affected the relations between Macao and Manila and gave rise to new possibilities of cooperation and mutual trade. This paper will analyse and give new evidence to the political and economic role of the Macao-Manila route throughout the period of the Iberian Union (1580-1640), according to the developments of the Portuguese trade network via Luzon and the fight against the Dutch and English East India Companies.