Pánfilo participated in the conquest of Cuba and led an expedition to Camagüey, escorting Bartolomé de las Casas.

Bartolomé de las Casas described him as "a man of authoritative personality, tall of body and somewhat blonde inclined to redness".

De las Casas (who was an eyewitness) reported that Narváez presided over the massacre of Caonao, where Spanish troops killed a village full of natives who had come to meet them with food.

"[This quote needs a citation] Diego Velázquez de Cuéllar, the governor of Cuba, sponsored Hernán Cortés to man an expedition to Mexico in 1519.

[8]: 280–281 Narváez disembarked at Veracruz, where Cortés had left a small garrison and set out with the rest of his men for the Aztec capital of Tenochtitlan.

Narváez continued along its coastline and arrived at the main village of the Tocobaga Indians (present-day Safety Harbor), where he discovered "many boxes from Castile" and several European artefacts.

Recent research suggests that he may have found the remnants of the 1521 settlement established and abandoned by Juan Ponce de León.

Unable to find the gold and other riches he sought and tired of hostilities with the natives, Narváez ordered the construction of four rafts in an attempt to reach Pánuco (his original destination).

It was eight years from their initial landing in Florida before they arrived in Culiacán (Sinaloa), where they found Melchor Diaz mayor and captain of the province.

Cabeza de Vaca wrote a relación[11] about the journey on foot by these four survivors across the present-day southwestern United States and northern Mexico.