The school's campus is situated on land adjoining the Adelaide Botanic Garden and the former site of the Royal Adelaide Hospital and is partly built from the structure of the old Reid Building from the University of South Australia.

[2] Adelaide Botanic High School opened on 29 January 2019 under the leadership of Foundation Principal Alistair Brown, who had previously held the role of Principal at Heathfield High School in the Adelaide Hills.

The school opened on the site of what was previously known as the Reid Building, which housed the University of South Australia's School of Pharmacy and Medical Sciences before its relocation to the university's City East campus.

Both of these buildings are conjoined by a six-storey atrium which includes several multipurpose learning areas.

Facilities at Adelaide Botanic High School include: On 24 August 2021, a 13-year-old school boy was charged with aggravated assault, carrying a dangerous weapon and common assault, after stabbing another student with scissors.