Belshazzar played a pivotal role in the coup d'état that overthrew the king Labashi-Marduk (r. 556 BC– ) and brought Nabonidus to power in 556 BC.

Belshazzar also lacked many of the prerogatives of kingship, most importantly he was not allowed to preside over and officiate the Babylonian New Year's festival, which was the exclusive right of the king himself.

[10] It is alternatively possible that later traditions of Belshazzar being a descendant of Nebuchadnezzar are derived from royal propaganda, and that there was no connection to the previous ruling Chaldean dynasty.

[12] As all of these ancient Babylonian documents were written after Babylon was conquered by the Achaemenid Empire, they are biased in favor of Cyrus, and against Nabonidus and Belshazzar.

[17] After the accession of his father, Belshazzar emerges in the sources as a prominent businessman and the head of a wealthy household, a role that was typically not picked up by members of the royal family in the Neo-Babylonian period.

Whereas Neriglissar's career as a businessman prior to becoming king can be followed through a trail of surviving business documents, Belshazzar appears to have become a prominent member of the Babylonian oligarchy overnight[18] (Belshazzar, in contrast to his co-conspirators was notably not a member of the old Babylonian aristocracy),[19] not being mentioned in any business documents or private transactions prior to Nabonidus becoming king.

[22] As he was clearly the main beneficiary of the coup, Belshazzar was likely the chief orchestrator of the conspiracy ended in the deposition and death of Labashi-Marduk.

[24] Nabonidus made Tayma his provisional seat and he would stay there for about a decade, not returning to Babylon until September or October of 543 or 542 BC.

[30] Though it is clear that Belshazzar during his father's absence assumed many responsibilities typically only held by the king,[22] several prerogatives were also kept solely by Nabonidus.

It is clear that the New Year's festival was not celebrated, and that there was concern regarding the rising power of the Achaemenid Empire under Cyrus the Great.

[41] As Nabonidus's stay in Tayma continued, Belshazzar became acutely aware of the threat presented by the Achaemenids, as he is recorded as having expended resources at projects in Sippar and nearby defenses.

The fall of Lydia in 546 BC meant that the Neo-Babylonian Empire was now effectively encircled by a stronger kingdom which had nearly unlimited resources at its disposal.

Nabonidus also had certain inscriptions made during the period of the regency edited to add prayers urging Belshazzar and the people of Babylonia to accept and receive Sîn's blessing.

One possibility, suggested by Paul-Alain Beaulieu, is that Belshazzar was put in charge of Babylonia's defense and was moving with the army along the northern and eastern border.

After a decisive victory at the battle of Opis, the Persian army, on 12 October,[48] led by Ugbaru, entered Babylon without a fight.

[8] The later authors of the Talmud and the Midrash emphasize the tyrannous oppression of his Jewish subjects, with several passages in the Prophets interpreted as referring to him and his predecessors.

The Babylonian kings are often mentioned together as forming a succession of impious and tyrannical monarchs who oppressed Israel and were therefore foredoomed to disgrace and destruction.

The command given to Abraham to cut in pieces three heifers (Genesis 15:9) as a part of the covenant established between him and his God was thus elucidated as symbolizing Babylonia, which gave rise to three kings, Nebuchadnezzar, Amel-Marduk, and Belshazzar, whose doom is prefigured by this act of "cutting to pieces" (Midrash Genesis Rabbah xliv.).

Belshazzar, being greatly alarmed at the mysterious handwriting on the wall, and apprehending that someone in disguise might enter the palace with murderous intent, ordered his doorkeepers to behead anyone who attempted to force an entrance that night, even though such person should claim to be the king himself.

Suiting the action to the word, Cyrus and Darius grasped a heavy ornament forming part of a candelabrum, and with it shattered the skull of their royal master (Shir ha-Shirim Rabbah 3:4).