The annual affair of the raid and plunder of Vijayanagar towns and villages by the Deccan sultans came to an end during the Raya's rule. In 1509 Krishnadevaraya's armies clashed with the Sultan of Bijapur at Diwani and the Sultan Mahmud was severely injured and defeated. Yusuf Adil Khan was killed and the Raichur Doab was annexed. Taking advantage of the victory and the disunity of the Bahamani Sultans, the Raya invaded Bidar, Gulbarga and Bijapur and earned the title "establisher of the Yavana kingdom" when he released Sultan Mahmud and made him de facto ruler. The Sultan of Golconda Sultan Quli Qutb Shah was defeated by Timmarusu who was the prime minister of Sri Krishnadevaraya .

Krishna Deva Raya established friendly relations with the Portuguese, who set up the Portuguese Dominion of India in Goa in 1510. The Emperor obtained guns and Arabian horses from the Portuguese merchants. He also utilized Portuguese expertise in improving water supply to Vijayanagara City.

The Surya Vamsi Gajapatis of Odisha ruled a vast land comprising Andhra region, Odisha. Krishna Deva Raya's success at Ummatur provided the necessary impetus to carry his campaign into Coastal Andhra region which was in control of Gajapati Prataparudra Deva. The Vijayanagar army laid siege to the Udayagiri fort in 1512. The campaign lasted for a year before the Gajapati army disintegrated due to starvation. Krishna Deva Raya offered prayers at Tirupati thereafter along with his wives Tirumala Devi and Chinnama Devi. The Gajapati army was then met at Kondaviduraju where the armies of Vijayanagara, after establishing a siege for a few months and heavy with initial defeats began to retreat, until Timmarusu upon discovering a secret entrance to the unguarded eastern gate of the fort launched a night attack culminating with the capture of the fort and the imprisonment of the greatest swordsman of his time, Prince Virabhadra, the son of Gajapati Emperor of Kalinga-Utkal,Gajapati Prataprudra Deva. Saluva Timmarasa took over as governor of Kondavidu thereafter. The Vijayanagar army then accosted the Adapa Kamma dynasty army allies to Gajapatis at Kondapalli area and laid another siege. Krishnadevaraya then planned for an invasion of mainland Kalinga-Utkal but the Gajapati Emperor, Prataparudra, privy of this plan had built up a strategy to rout the Vijayanagara army and along with it its king, Krishnadevaraya. The confrontation was to happen at the fort of Kalinganagar. But the wily Timmarusu secured the information by bribing a Telugu deserter, formerly under the Service of the mighty Prataprudra deva. Prataprudra was driven to Cuttack, the capital of the Gajapati empire and eventually surrendered to Vijaynagar, giving his daughter Princess Annapurna Devi in marriage to Sri Krishna Deva Raya. As per treaty Krishna river became boundary of Vijaynagar and Odisha Kingdom. Thereafter peace between the two strongest Hindu empires in India ensured a period of harmony and the safety of Sanatana dharma in India.

The highlight of his conquests occurred on 19 May 1520 where he secured the fortress of Raichur from Ismail Adil Shah of Bijapur after a difficult siege during which 16,000 Vijaynagar Soldiers were killed. The exploits of the chief military commander, Pemmasani Ramalinga Nayudu, during the battle of Raichur were suitably rewarded by the grateful Emperor. During the campaign against Raichur, it is said that 703,000 foot Soldiers, 32,600 cavalry and 551 elephants were used (See The battle of Raichur). Finally, in his last battle, he razed to the ground the fortress of Gulburga, the early capital of the Bahmani sultanate. His empire extended over the whole of South India.

In 1524 he made his son Tirumala Raya the Yuvaraja though the crown Prince did not survive for long. He was poisoned to death. Suspecting the involvement of Timmarusu, Krishna Deva Raya had his trusted commander and adviser blinded. At the same time, Krishnadevaraya was preparing for an attack on Belgaum that was in the Adil Shah’s possession; Krishnadevaraya took seriously ill. He died soon after in 1529. Before his death, he nominated his brother, Achyuta Deva Raya as his successor. The rule of Krishnadevaraya was a glorious chapter in the history of Vijayanagara Empire. Even the ruins at Hampi tell the glorious tale of that mighty empire [Citations needed].

During his reign he kept a strict control over his ministers who were severely punished for any misdeeds. He abolished some of the obnoxious taxes such as the marriage fee. To increase the revenue he brought new lands under cultivation by ordering deforestation of some areas. A large-scale work to obtain water for irrigation around Vijayanagar was also undertaken by him. Foreign travelers such as Paes, Nunez and Barbosa who visited Vijayanagar speak highly of the efficiency of administration and prosperity of the people during his reign. In spite of his preoccupations with the defense and reorganization of the territories conquered by him, he founded a new town called Nagalapur. Paes summarises the king's attitude to matters of law and order by the sentence, "The king maintains the law by killing." Offences against property (designed to maintain stability) and for murder ranged from cutting of a foot and hand for theft and beheading for murder (except for those occurring as a result of duel). Paes could not estimate the size of Vijaynagar as his view was obscured by the hills but estimated the city to be at least as large as Rome. Furthermore, he considered Vijaynagar to be "the best provided city in the world" with a population of not less than a half a million. The empire was divided into a number of provinces often under members of the royal family and into further subdivisions. The administrative languages of the Empire were Kannada and Telugu—the latter was also the Court language. Telugu was a popular literary medium, reaching its peak under the patronage of Krishnadevaraya.