Raghavendra was born as Venkatanathan in the town of Bhuvanagiri, Tamil Nadu into a family of musicians and scholars. His great-grandfather Krishnabhattar was a tutor to Vijayanagara king Krishnadeva Raya and his father Timmanacharya was an accomplished scholar and musician. After the fall of the Vijayanagara empire, Timmanacharya migrated to Kanchi with his wife Gopikamba. Venkatanatha had two siblings: Gururaja and Venkatamba. Venkatanatha's education was undertaken by his brother-in-law Lakshminarasimhacharya, after the early demise of his father and he was subsequently married.
According to Raghavendra Vijaya, his triumph in debates at Thanjavur attracted the attention of Sudhindra Tirtha, the erstwhile pontiff of Kumbakonam mutt. Though initially uncertain about the prospect of renunciation, Venkatanatha relented to Sudhindra's demands and was ordained as a monk in 1621. After the passing away of Sudhindra Tirtha in 1623, Venkatanatha succeeded him as the pontiff the mutt and took on the name Raghavendra Tirtha. He undertook a pilgrimage visiting places including Udupi, Kolhapur, and Bijapur. He received grants from Dodda Kempadevaraja and settled down in the village of Mantralayam, which was presented to him by the Governor of Adoni. In 1801, while serving as the Collector of Bellary, Thomas Munro is believed to have come across an apparition of Raghavendra. He died in 1671 and his mortal remains are enshrined in Mantralayam. He was succeeded by his sishya, Sri Yogendra Tirtha.