Selim II broke with tradition by sending only his oldest son out of the palace to govern a province, assigning Murad to Manisa.

He made the proposition of making Morocco an Ottoman vassal in exchange for the support of Murad III in helping him gain the Saadi throne.

[7][5][8] Abd al-Malik made a deal with the Ottoman troops by paying them a large amount of gold and sending them back to Algiers, suggesting a looser concept of vassalage than Murad III may have thought.

[5] Murad's name was recited in the Friday prayer and stamped on coinage marking the two traditional signs of sovereignty in the Islamic world.

[10][11] Abd al-Malik died in 1578 and was succeeded by his brother Ahmad al-Mansur who formally recognised the suzerainty of the Ottoman Sultan at the start of his reign while remaining de facto independent.

[12][13] The Ottomans had been at peace with the neighbouring rivaling Safavid Empire since 1555, per the Treaty of Amasya, that for some time had settled border disputes.

But in 1577 Murad declared war, starting the Ottoman–Safavid War (1578–1590), seeking to take advantage of the chaos in the Safavid court after the death of Shah Tahmasp I. Murad was influenced by viziers Lala Kara Mustafa Pasha and Sinan Pasha and disregarded the opposing counsel of Grand Vizier Sokollu.

Murad also fought the Safavids which would drag on for 12 years, ending with the Treaty of Constantinople (1590), which resulted in temporary significant territorial gains for the Ottomans.

To keep up with changing military techniques, the Ottomans trained infantrymen in the use of firearms, paying them directly from the treasury.

By 1580 an influx of silver from the New World had caused high inflation and social unrest, especially among Janissaries and government officials who were paid in debased currency.

[18]: 39  In one correspondence, Murad entertained the notion that Islam and Protestantism had "much more in common than either did with Roman Catholicism, as both rejected the worship of idols", and argued for an alliance between England and the Ottoman Empire.

[18]: 40  To the dismay of Catholic Europe, England exported tin and lead (for cannon-casting) and ammunition to the Ottoman Empire, and Elizabeth seriously discussed joint military operations with Murad III during the outbreak of war with Spain in 1585, as Francis Walsingham was lobbying for a direct Ottoman military involvement against the common Spanish enemy.

The Ottoman historian Mustafa Selaniki wrote that whenever Murad planned to go out to Friday prayer, he changed his mind after hearing of alleged plots by the Janissaries to dethrone him once he left the palace.

Murad's personal physician Domenico Hierosolimitano described a typical day in the life of the sultan: In the morning he rises at dawn to say his prayer for half an hour, then for another half-hour he writes.

His monogamy was disapproved of by Nurbanu Sultan, who worried that Murad needed more sons to succeed him in case Mehmed died young.

"The arrow [of Murad], [despite] keeping with his created nature, for many times [and] for many days has been unable to reach at the target of union and pleasure," wrote Mustafa Ali.

Court physicians, working under Nurbanu's orders, eventually prepared a successful cure, but a side effect was a drastic increase in sexual appetite; by the time Murad died, he was said to have fathered over a hundred children.

Murad dreams of various activities, including being stripped naked by his father and having to sit on his lap,[2]: 72  single-handedly killing 12,000 infidels in battle,[2]: 99  walking on water, ascending to heaven, and producing milk from his fingers.

[2]: 143 In another letter addressed to Şüca Dede, Murad wrote "I wish that God, may He be glorified and exalted, had not created this poor servant as the descendant of the Ottomans so that I would not hear this and that, and would not worry.

Murad died from what is assumed to be natural causes in the Topkapı Palace on 16 January 1595 and was buried in a tomb next to the Hagia Sophia.

Murad had his mother Nurbanu buried next to her husband Selim II, making her the first consort to share a sultan's tomb.