King Manuel I of Portugal sent a fleet commanded by Pedro Alvares Cabral to Calicut, India. While the alleged purpose of the trip was to trade spices, the Assassin's Guild in Calicut felt that it was a threat against them and requested the aid of the Brotherhood in Italy.

Traveling to the Indian trade hub, the Assassins prepared to combat the Portuguese King's secret Templar agenda. Posing as workers, the Assassins rallied the citizens against Cabral and eliminated his commanders before driving him out of the city.

Furious over the defiance his forces experienced in Calicut, Manuel commissioned a ruthless response in the form of a large fleet led by Vasco de Gama. Unprepared to deal with the impending attack, the Assassins were forced to clear out the guild, hide their relics and documents, and help evacuate family and friends. When Gama's fleet arrived, their assault was relentless. He demanded the expulsion of Muslims, incited violence, and slaughtered hundreds of innocent men, women, and children.

Presuming the operation a success, de Gama returned to Portugal, leaving his most trusted generals to continue his work in the city. Despite the violence, the Brotherhood endured. They stealthily eliminated their oppressors with the help of the local population, crippling Manuel's efforts to remove the Assassin presence.