Orianthi Panagaris was born in Adelaide, South Australia, and is of Greek descent. She began playing piano at the age of three and, at the encouragement of her father, moved to acoustic guitar at the age of six. When she was eleven, she took up electric guitar and left her school, Mercedes College, enrolling at Cabra Dominican College. She also attended St Peter's Collegiate Girls' School for a short period. At the age of 15, she turned her focus to writing songs and so began her professional career. She has been playing in bands since the age of 14 and performed in her first stage show for Steve Vai at the age of 15. Orianthi met and jammed with Carlos Santana when she was 18. He invited Orianthi to get up and jam with him at soundcheck then later asked if she would join him on stage that night to jam at his Adelaide concert, Memorial Drive on 30 March 2003.

Orianthi independently released her debut studio album, Violet Journey in 2005, composing all the material, contributing guitar, vocals and drums on most cuts. She produced and mixed the final product at her home studio. Carlos Santana brought Orianthi to Paul Reed Smith's attention which led to her endorsement. Orianthi relocated to Los Angeles, signed with Geffen Records in late 2006 and struck a management deal with 19 Entertainment.

Orianthi started working on her major label debut Believe in 2007 which was released in October 2009. The album produced the worldwide hit "According to You", which was the Single of the Week on iTunes on 27 October 2009, reached number 2 on US radio airplay and charted to number eight in Australia, three in Japan, and achieved platinum status in the US and Australia. The charismatic rock instrumental "Highly Strung" featuring Steve Vai became a popular YouTube video with millions of views and climbing, and her song "Suffocated" was featured on Guitar Hero: Warriors of Rock as a playable song. Orianthi followed up with a four-song EP including two singles "Shut Up and Kiss Me" and "Courage".

Orianthi met with Little Kids Rock students at the annual trade show for music merchants (NAMM) in 2010 after they opened for her. The kids gave her an acoustic guitar they autographed and she joined LKR's Honorary Board.

On 29 August 2011, Orianthi was announced as Alice Cooper's new Guitarist. She replaced Damon Johnson, who is now a member of Thin Lizzy. She was the first female member of the Alice Cooper band. Orianthi did two world tours with Alice Cooper, but resigned in June 2014 to be replaced by Nita Strauss.

Orianthi has appeared as a Guitarist for other stars including shows with Michael Bolton, Dave Stewart and James Durbin. She also appeared on the Top 7 week season 12 of American Idol on 3 April 2013 to play guitar for each of the performances. One month later Orianthi performed Fine China with Chris Brown at the 2013 Billboard Music Awards, and on 8 December of that same year she paid tribute to Carlos Santana, performing in the Kennedy Center Honors Gala. She spent most of 2013-2015 touring with Dave Stewart, started BeMyBand, and released a song. In 2014, she joined Richie Sambora for his solo tour in Australia and Europe. In 2016, the two toured under the name RSO in Australia, South America and England. The pair released the EP Rise on 29 September 2017.

Orianthi joined supergroup Hollywood Vampires on the track "Whole Lotta Love" for the band's 2015 self-titled debut album.

In October 2016, Orianthi featured in The 2016 NRL Grand Final pre game entertainment alongside Richie Sambora. Their performance was met with mixed reviews with Sambora having to come out and defend their performance the following day online.

In September 2017, Orianthi and Richie Sambora released a five-song EP called Rise under the name RSO.