16世紀，西班牙的殖民擴張的主要對象是美洲。哥倫布所到之處，他都以西班牙國王的名義宣佈加以占領。加勒比海許多島嶼首先淪為西班牙的殖民地。隨着地理探測的進展，西班牙殖民者迅速侵占了美洲的廣大地區。
1517年，西班牙人憑藉炮火的威力，想在墨西哥尤卡坦的察姆坡登陸，由於印第安人的反擊而沒有成功。1518年另一夥西班牙侵略者想在這裏登陸，又遭到失敗。
1519年，西班牙貴族、冒險傢費爾南多·科爾蒂斯率領一小支軍隊在墨西哥東岸登陸，開始殖民徵服。他們劫奪印第安人的金銀財寶，屠殺印第安人。印第安人在他們的領袖考特莫剋領導下，進行了不屈的鬥爭，打敗了科爾蒂斯，半數以上的西班牙殖民軍被殲滅。在戰鬥中，印第安人民像對待侵略者一樣，用石塊擊斃了出賣民族利益投靠敵人的國王孟特祖瑪。
1521年，西班牙重兵壓境，猛攻特諾奇蒂特蘭城（今墨西哥城），印第安人民在考特莫剋的領導下，為保衛自己的首都是進行了英勇戰鬥。抗戰進行了數月之久，於9月13日，特諾奇蒂特蘭城纔被西班牙殖民軍攻破。
考特莫剋被捕後，敵人嚴刑拷問，要他說出金銀埋藏之地，他始終沉默不答。這位印第安人領袖、墨西哥的民族英雄，被殖民強盜絞殺了。
1519年，西班牙入侵墨西哥，1521年，阿茲特剋首都 Tenochtitlan被西班牙和阿茲提剋的主要敵人Tlaxcaltecs徵服。但是西班牙並沒有完全徵服阿茲提剋，而是在兩世紀後纔完成，有兩個主要原因使西班牙人勝利。
1. 阿茲提剋人因為相信要有恆定的活人犧牲，宇宙纔會持續運作，所以每一年都犧牲了許多人，這一些人大多來自戰爭的戰俘。但在和平的時候，阿茲提剋人訴諸一種形式上的“禮戰”，已獲得戰俘。因此Tlaxcalteca纔會心甘情願加入西班牙對付阿茲提剋人的的部隊 。
2. 另一個重要因素，西班牙人帶入各種瘟疫和傳染病帶到美洲，天花、流感、鼠疫、麻疹，數以十萬計的土人受到感染，這些流行病可能造成大約八百萬當地人死亡。
In 1519, the Aztec civilization of what now is known as Mexico was invaded by Spain, and two years later in 1521, the Aztec capital of Tenochtitlan was conquered by an alliance between Spanish and Tlaxcaltecs (the main enemies of Aztecs). Francisco Hernández de Córdoba explored the shores of South Mexico in 1517, followed by Juan de Grijalva in 1518. The most important of the early Conquistadores was Hernán Cortés, who entered the country in 1519 from a native coastal town which he renamed "Puerto de la Villa Rica de la Vera Cruz" (today's Veracruz).
Contrary to popular opinion, Spain did not conquer all the empire when Cortes conquered Tenochtitlan in 1521. It would take another two centuries after the Siege of Tenochtitlan before the Conquest of the Aztec Empire would be complete, as rebellions, attacks, and wars continued against the Spanish by other native peoples.
Role of religion in the fall of the Aztec Empire
The Aztecs' religious beliefs were based on a great fear that the universe would cease functioning without a constant offering of human sacrifice. They sacrificed thousands of people on special occasions. This belief is thought to have been common throughout Nahuatl people. In order to acquire captives in times of peace, the Aztec resorted to a form of "ritual warfare", or flower war. Tlaxcalteca and other Nahuatl nations were forced into such wars, and, not particularly liking the idea of being a perpetual source of human sacrifices, they willingly joined the Spaniard forces against the Aztecs. The small Spanish force, consisting of 508 men schooled in European warfare and equipped with steel weapons and armor, was reinforced with thousands of indigenous Indian allies. Their use of ambush during indigenous ceremonies allowed the Spanish to avoid fighting the best native warriors in direct armed battle, such as during The Feast of Huitzilopochtli.