From the outset of his reign, Sigismund came into collision with the country's nobility, who had already begun curtailing the power of the great families. The ostensible cause of the nobility's animosity to the King was his second marriage, secretly contracted before his accession to the throne, with (said to be beautiful) Lithuanian Calvinist, Barbara Radziwiłł, daughter of Hetman Jerzy Radziwiłł.

But the real forces behind the movement seem to have been the Austrian court and Sigismund's own mother, Bona Sforza, and so violent was the agitation at Sigismund's first sejm (31 October 1548) that the deputies threatened to renounce their allegiance unless the King repudiated his wife Barbara. He refused, and his moral courage and political dexterity won the day.

By 1550, when Sigismund summoned his second Sejm, a reaction had begun in his favor, and the nobility was rebuked by Piotr Kmita, Marshal of the Sejm, who accused them of attempting to unduly diminish the legislative prerogatives of the crown.

The death of Queen Barbara, five months after her coronation (7 December 1550), under distressing circumstances which led to a suspicion that she had been poisoned by Bona Sforza, compelled Sigismund to contract a third, purely political union with his first cousin, the Austrian archduchess Catherine, also the sister of his first wife, Elisabeth, who had died within a year of her marriage to him, while he was still only crown prince.

The third bride was sickly and unsympathetic, and Sigismund soon lost all hope of children by her — to his despair, for as he was the last male Jagiellon in the direct line, the dynasty was threatened with extinction. He sought to remedy this by liaisons with two of the most beautiful of his countrywomen, Barbara Giżanka and Anna Zajączkowska. The sejm was willing to legitimatize, and acknowledge as Sigismund's successor, any male heir who might be born to him; however, the King was to die childless.

The King's marriage was a matter of great political import to Protestants and Catholics alike. Had Sigismund not been so good a Catholic, he might have imitated Henry VIII of England by pleading that his detested third wife was the sister of his first wife, and that consequently the union was uncanonical. The Polish Protestants hoped that he would do so and thus bring about a breach with Rome at the very crisis of the religious struggle in Poland; while the Habsburgs, who coveted the Polish throne, raised every obstacle to the childless King's remarriage. Not till Queen Catherine's death (28 February 1572) was Sigismund set free, but less than six months later he would follow her to the grave.

Sigismund's reign was a period of internal turmoil and external expansion. He saw the invasion of Poland by the Reformation, and the peero-cratic upheaval that placed all political power in the hands of the nobility; he saw the collapse of the Knights of the Sword in the north (which led to the Commonwealth's acquisition of Livonia) and the consolidation of Turkey's power in the south. Throughout this perilous transitional period, Sigismund successfully steered the ship of state amid the whirlpools that constantly threatened to engulf it. A less imposing figure than his father, the elegant and refined Sigismund II Augustus was nevertheless an even greater statesman than the stern and majestic Sigismund I the Old.

Sigismund II possessed to a high degree the tenacity and patience that seem to have characterized all the Jagiellons, and he added to these qualities a dexterity and diplomatic finesse which he may have inherited from his Italian mother. No other Polish king seems to have so thoroughly understood the nature of the Polish sejm. Both the Austrian ambassadors and the papal legates testify to the care with which he controlled his nation. Everything went as he wished, they said, because he seemed to know everything in advance. He managed to get more money than his father ever could, and at one of his sejms he won the hearts of the assembly by unexpectedly appearing before them in the simple grey coat of a Masovian lord. Like his father, a pro-Austrian by conviction, he contrived even in this respect to carry with him the nation, always distrustful of the Germans, and thus avoided serious complications with the dangerous Turks.

Sigismund II mediated for twenty years between the Roman Catholic Church and the Protestants without alienating the sympathies of either. His most striking memorial, however, may have been the Union of Lublin, which finally made of Poland and Lithuania one body politic, the Polish - Lithuanian Commonwealth — the "Republic of the Two Nations" (Polish: Rzeczpospolita Obojga Narodów, Lithuanian: Abiejų Tautų Respublika). Also, German speaking Royal Prussia and Prussian cities were included. This achievement might well have been impossible without Sigismund.

Sigismund died at his beloved Knyszyn on 6 July 1572, aged 51. In 1573, Henry III of Valois was elected King of the Polish - Lithuanian commonwealth for a few months, but then returned to France where he was crowned King Henry III of France. Shortly thereafter, Sigismund's sister Anna of Poland married Stefan Batory, and they ruled as King and Queen of Poland.

In addition to his family connections, Sigismund II was allied to the Imperial Habsburgs by his pledge as member of the Order of the Golden Fleece.

Sigismund Augustus carried on with the development of several royal residencies including Wawel Castle, Vilnius Castle, Niepołomice Castle and the Royal Castle in Warsaw. In the 1560s he acquired the Tykocin Castle and rebuilt it in Renaissance style. During the reign of Sigismund Augustus the structure served as a royal residence with an impressive treasury and library as well as the main arsenal of the crown. Sigismund Augustus was a passionate collector of jewels. According to nuncio Bernardo Bongiovanni's relation, his collection was allocated in 16 chests. Among the precious items in his possession was Charles V's ruby of 80 000 scudos' worth, as well as the Emperor's diamond medal with Habsburgs Eagle on one side and two columns with a sign Plus Ultra on the other side. In 1571, after the death of his nephew John II Sigismund Zápolya, he inherited the so-called Hungarian Crown and the so-called Swedish Crown was made for him. The Polish king treated those crowns as a family keepsake, and kept them in a private vault in the Tykocin Castle. He had also a sultan's sword of 16 000 ducats' worth, 30 precious horse trappings and 20 different private use armours. The king's possession included a richcollection of tapestries (360 pieces), commissioned by him in Brussels in the years 1550 - 1560.

He married three times:

• On 5 May 1543, Sigismund married his first wife Elisabeth of Austria (9 July 1526 – 15 June 1545), eldest daughter of Ferdinand I, Holy Roman Emperor and Anna of Bohemia and Hungary.
• Between 28 July and 6 August 1547, Sigismund married his second wife Barbara Radziwiłł (6 December 1520 – 8 May 1551).
• In the summer of 1553, Sigismund married Catherine of Austria (15 September 1533 – 28 February 1572), a younger sister of his first wife.