Columbus returned to Spain, physically and mentally exhausted. Queen Isabella, his main supporter, died in November 1504. Her death significantly diminished Columbus's influence and his ability to secure further royal patronage.

Columbus spent his final years fighting legal battles to reclaim his titles and the rights granted to him in the Capitulations of Santa Fe. He believed that he was entitled to a significant share of the wealth generated by the lands he had discovered, but he faced resistance from the Spanish Crown.

Christopher Columbus died in Valladolid, Spain, on May 20, 1506. He was around 54 years old. Despite his achievements, he died a relatively disillusioned man, still convinced that he had reached Asia and not a new continent.