The hospital was officially opened by Minister Mentor Lee Kuan Yew on 15 November 2010, but began seeing outpatients and day surgery patients on 28 March that year.

The hospital offers an extensive range of medical services and healthcare options for residents living in the north.

[3] On 30 September 2007, then-Health Minister Khaw, at a community event in Yishun, noted that additional land parcels set aside around the Khoo Teck Puat Hospital could be used for construction of further, more specialised health-care facilities and that beyond 2020, might eventually create a health-care cluster similar to the diverse facilities now in the vicinity of Singapore General Hospital, providing high-quality healthcare services to the growing population in the north.

The Khoo Teck Puat Hospital was designed by CPG Consultants[8] in collaboration with RMJM to be patient-friendly.

Wind tunnel tests conducted at the National University of Singapore found that the "fins" would enhance the air flow by 20 to 30%.

In 2015, Muhammad Iskandar Sa'at, a suspect arrested for motor theft, was being evaluated at KTPH for chest pain while under custody.

Iskandar was initially charged for an unlawful discharge of a firearm under the Arms Offences Act, which carries the mandatory death penalty,[12] but the charge was reduced to an unlawful possession of a firearm for causing hurt to a public servant, which carries a mandatory life sentence.