After his father's death in 1997, Patnaik won the Aska Lok Sabha by-election. In December 1997 he split from the Janata Dal and founded the Biju Janata Dal, named after his father. He was re-elected from Aska in 1998 and 1999 and served as Union Minister of Steel and Mines (1998–1999) and then Mines and Minerals (until March 2000) in the Vajpayee government.
Patnaik became Chief Minister on 5 March 2000 and won five consecutive terms:
| Term | Period | BJD assembly seats |
|---|---|---|
| 1st | 2000 – 2004 | In alliance with BJP |
| 2nd | 2004 – 2009 | In alliance with BJP |
| 3rd | 2009 – 2014 | 103 of 147 |
| 4th | 2014 – 2019 | 117 of 147 |
| 5th | 2019 – 2024 | 112 of 146 |
In 2009 the BJD ended its alliance with the BJP after the 2008 Kandhamal violence and went on to win on its own. His 24 years in office are the second-longest for any Indian chief minister, after Pawan Kumar Chamling of Sikkim.
In the 2024 elections the BJD lost power to the BJP, winning 51 seats. Patnaik lost Kantabanji, his first electoral defeat, but retained Hinjili. On 20 June 2024 he became the Leader of the Opposition, and in 2025 he was re-elected BJD president for the ninth time. In March 2026 he demanded the resignation of Odisha's health minister after a deadly fire at SCB Medical College and Hospital in Cuttack.
Critics pointed to his limited fluency in Odia, noting that he read Odia speeches written in Roman script. His health also became a political issue during the 2024 campaign; he said he was in good health.