Raimondello was the second son of Nicolo Orsini di Nola (1331-1399), 3rd Count of Nola, grand Justiciar and also Grand Chancellor of Kingdom of Naples, and his second wife Maria del Balzo (of counts of Soleto). His grandfather was Roberto Orsini di Nola (1295-1345), 2nd Count of Nola, Grand Justiciar of Naples, and grandmother was the remarkable heiress Sveva del Balzo (born in first years of 14th century), Countess of Soleto, heiress of des Baux because of whom the family is later known as del Balzo Orsini. His full brother Roberto was 4th Count of Nola, died 1400 and left only illegitimate issue, however natural son inherited County of Nola and became Grand Justiciar. One of his sisters, Sveva, married Francesco del Balzo, Duke of Andria.
In 1384 he married Mary of Enghien (1367- 9 May 1446), Countess of Lecce, daughter and (after her brother) heiress of Count John, Lord of Nivelles, Presle, Omophita and Diskoria, and his wife Bianca del Balzo dei Duchi d'Andria.
Raimondello became the richest Italian feudal lord of his era. The principality of Taranto included half of the Kingdom of Naples, and the Prince ruled almost independently from the king. For this reason, a struggle between Raimondello and King Ladislas of Naples, who enventually ruled over the principality by marrying Mary after Raimondello's death.
Raimondello ordered the construction of the church of Santa Caterina d'Alessandria in Galatina, a masterpiece of Franciscan art. He is buried in the church, together with his son and heir Giovanni Antonio.
Raimondello and Mary had the following children: