He made his debut with Sekhar Kammula's coming-of-age blockbuster drama Happy Days (2007), and went on to star in films such as Kotha Bangaru Lokam (2008), Kurradu (2009), Yemaindi Ee Vela (2010), D for Dopidi (2013), Pandavulu Pandavulu Thummeda (2014), Mama Manchu Alludu Kanchu (2015), Michael (2023) and Nindha (2024).

[2] Varun Sandesh is the grandson of noted Telugu writer Jeedigunta Ramachandra Murthy, who worked for All India Radio for 28 years in Hyderabad.

[9] In 2007, Sandesh applied for auditions for a Sekhar Kammula film through an online advertisement, despite having no prior acting experience and previously planning to pursue medical studies.

[13][14] He then starred in romantic drama Kotha Bangaru Lokam (2008), which received critical acclaim and went on to become one of the biggest blockbusters of the year.

In 2019, Sandesh became a notable television personality for his participation in Star Maa's reality TV show Bigg Boss Telugu 3, reaching the grand finale and finishing in 4th place.