At the time Beltrán de Guzmán was serving as governor of Pánuco, so Charles ordered the judges to assemble in Veracruz and from there make a joint entrance into the capital. The four from Spain, however, did not wait for the arrival of Beltrán, and proceeded directly to the capital. They arrived on December 8, 1528, taking over the government on the following day. They were given a splendid reception by the city government. Beltrán arrived a little after the others. Two of them (Maldonado and Parada) were sick on their arrival and soon died. They did not take part in the government.
The instructions given to the Audiencia included a recommendation for good treatment of the Indigenous and a directive that the investigation into the conduct of Cortés and his associates Pedro de Alvarado, Alonso de Estrada, Rodrigo de Albornoz, Gonzalo de Salazar and Pedro Almíndez Chirino be concluded within 90 days. Most of these associates had participated in the government in the proceeding few years while Cortés was in Honduras, with a lot of in-fighting among themselves and injustices to the population, both Spanish and Indigenous.
Cortés himself was now in Spain, where he was defending his conduct and appealing his loss of authority to Charles. (Both the previous governor, Alonso de Estrada, and Nuño Beltrán de Guzmán were enemies of Cortés.) Cortés had some success with his appeal, being named Marqués del Valle de Oaxaca and receiving some other honors.
Nevertheless, Beltrán de Guzmán was now in charge in New Spain. Among his official acts was placing plaques bearing the royal coat of arms on the principal buildings of the capital, to stress that sovereignty resided in the king, not in Cortés. He had Pedro de Alvarado arrested for questioning the loyalty of Gonzalo de Salazar. There was already some animosity between Cortés and Beltrán, because the former had been reluctant to recognize the latter as governor of Pánuco. The later events made the two enemies.
The Audiencia also banned direct communication with the court in Spain. This was so effective that Bishop Zumárraga felt the necessity of hiding a letter sealed in wax in a cask, to be smuggled to the Spanish authorities by a confederate sailor.
His motives for leaving the capital are unclear. Was he simply in search of riches, to be stolen from the native peoples? Or was he fearful of Cortés's return? The latter had been reappointed captain general, and was returning to the colony.
This expedition has been described as a "holocaust". Typically, the conquistadors attacked an Indian village, stole the maize and other food, razed and burned the dwellings, and tortured the native leaders to gather information on what riches could be stolen there, or from nearby populations. For the most part, these riches did not exist.
As an example, the Spanish were received in peace by Chief Tangáxuan II (called Caltzontzin by the Mexica) in the Tarascan state which is now the state of Michoacán. He gave Beltrán de Guzmán presents of gold and silver and supplied him with soldiers and provisions. Nevertheless, Beltrán de Guzmán had him arrested and tortured, to get him to reveal the location of hidden stores of gold. Presumably there was no more gold, because Tangáxuan did not reveal it under torture. Beltrán had him dragged by a horse and then burned alive.
The actions of the Audiencia attracted the attention of Juan de Zumárraga, bishop of Mexico, who put it under an ecclesiastical interdiction on March 7, 1530. The immediate cause of the interdiction was a case of violation of sanctuary. The Audiencia had violently taken from the convent of San Francisco a servant of Cortés accused of grave crimes, and two religious, Cristóbal de Angulo and García de Llerena.
Undeterred, Beltrán de Guzmán continued his violent assault on the peoples of the present-day states of Jalisco, Zacatecas, Nayarit and Sinaloa. In the latter state, he founded the city of San Miguel de Culiacán, on September 29, 1531. He returned to Tepic, where he set up his headquarters, sending out new expeditions from there. One of these founded the cities of Santiago de Galicia de Compostela and Purificación. Another traveled as far as the current state of Sonora. His violent expeditions into Chichimec lands were a main cause of the Mixtón rebellion.
This territory extended from the Rio Lerma to Sonora, with its capital at Compostela. New Galicia was a separate entity, not under the authority of the Audiencia of Mexico City (but still part of New Spain).
Beltrán continued his bloodbath in western and northern Mexico for seven years. During this time he explored and conquered a third of present-day Mexico. Many Indigenous were either slaughtered or sold into slavery in the Caribbean, earning Beltán de Guzmán the nickname "Bloody Guzmán". One nineteenth-century chronicler of the Conquest referred to Beltrán de Guzmán as "the detestable governor of Pánuco and perhaps the most depraved man ever to set foot in New Spain. Fray Bartolomé de las Casas called him a "great tyrant".