16世纪，西班牙的殖民扩张的主要对象是美洲。哥伦布所到之处，他都以西班牙国王的名义宣布加以占领。加勒比海许多岛屿首先沦为西班牙的殖民地。随着地理探测的进展，西班牙殖民者迅速侵占了美洲的广大地区。
1517年，西班牙人凭借炮火的威力，想在墨西哥尤卡坦的察姆坡登陆，由于印第安人的反击而没有成功。1518年另一伙西班牙侵略者想在这里登陆，又遭到失败。
1519年，西班牙贵族、冒险家费尔南多·科尔蒂斯率领一小支军队在墨西哥东岸登陆，开始殖民征服。他们劫夺印第安人的金银财宝，屠杀印第安人。印第安人在他们的领袖考特莫克领导下，进行了不屈的斗争，打败了科尔蒂斯，半数以上的西班牙殖民军被歼灭。在战斗中，印第安人民像对待侵略者一样，用石块击毙了出卖民族利益投靠敌人的国王孟特祖玛。
1521年，西班牙重兵压境，猛攻特诺奇蒂特兰城（今墨西哥城），印第安人民在考特莫克的领导下，为保卫自己的首都是进行了英勇战斗。抗战进行了数月之久，于9月13日，特诺奇蒂特兰城才被西班牙殖民军攻破。
考特莫克被捕后，敌人严刑拷问，要他说出金银埋藏之地，他始终沉默不答。这位印第安人领袖、墨西哥的民族英雄，被殖民强盗绞杀了。
1519年，西班牙入侵墨西哥，1521年，阿兹特克首都 Tenochtitlan被西班牙和阿兹提克的主要敌人Tlaxcaltecs征服。但是西班牙并没有完全征服阿兹提克，而是在两世纪后才完成，有两个主要原因使西班牙人胜利。
1. 阿兹提克人因为相信要有恒定的活人牺牲，宇宙才会持续运作，所以每一年都牺牲了许多人，这一些人大多来自战争的战俘。但在和平的时候，阿兹提克人诉诸一种形式上的“礼战”，已获得战俘。因此Tlaxcalteca才会心甘情愿加入西班牙对付阿兹提克人的的部队 。
2. 另一个重要因素，西班牙人带入各种瘟疫和传染病带到美洲，天花、流感、鼠疫、麻疹，数以十万计的土人受到感染，这些流行病可能造成大约八百万当地人死亡。
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.