Alfonso entered the Roman Curia in the household of Gian Pietro Carafa in 1548. His great-uncle continued to show him favour as pope, appointing him as an apostolic protonotary and insisting that the young boy sleep in his own private chambers. In March 1557 he was promoted to the cardinalate and a few weeks later made archbishop of Naples. After the disgrace of his uncles Carlo and Giovanni in January 1559, Alfonso assumed the role of Cardinal Nephew for the last few months of Paul's pontificate.

In June 1560 he was arrested on the instructions of the new pope Pius IV and along with his two uncles was imprisoned in the Castel Sant'Angelo on charges of corruption and the theft of papal property. However, receiving considerably more sympathy than his despised uncles, Alfonso was spared the execution that was their fate. In April 1561 he was released and in 1562 returned to his archdiocese.

He died of a fever on 29 August 1565 aged only twenty-five years.

• The Papacy And The Levant, Kenneth Meyer Setton, American Philosophical Society, 1984
• Miranda, Salvador. "CARAFA, Alfonso (1540-1565)". The Cardinals of the Holy Roman Church. Florida International University. OCLC 53276621.