He served as the Deputy Chief Minister of Sabah II from October 2020 to his promotion in January 2023 and the first term in the position in May 2018.

In January 2023, he was appointed as the Deputy Chief Minister I of Sabah succeeding Bung Mokhtar, who was dropped due to a political crisis (but retained his ministerial portfolio).

He is known to be a controversial politician, having been detained without trial under the Internal Security Act by the Barisan Nasional-controlled federal government under the leadership of then-Prime Minister, Mahathir Mohamad on suspicions of plotting to secede Sabah from the federation of Malaysia, although his defenders argue that this was a politically motivated move.

In 1990, he started his political career together with his brother Joseph Pairin Kitingan in Parti Bersatu Sabah (PBS).

[6] In the 2008 general election, he challenged his brother Tan Sri Datuk Seri Panglima Joseph Pairin from BN-PBS at the Keningau parliamentary constituency, but lost.

[26] Following the complaint, Prime Minister Mahathir Mohamad announced that they will not recognise the election in Sabah if corruption involved.

[33][34] During the 2020 Malaysian political crisis, Jeffrey supported Mahathir Mohamad to be reinstated as Prime Minister after his resignation.

[36] In late 2021, Mongabay reported that Jeffrey was involved in a carbon credit deal that was signed in October 2021 that declared 2 million hectares as protected areas, without the consultation of indigenous peoples residing there.

[37][38] Civil society groups and indigenous leaders were critical over the secrecy of the agreement and whether the carbon accrediting company, Hoch Standard, had prior experience to implement it.

In January 2021, Jeffrey tested positive for COVID-19 and underwent treatment at Queen Elizabeth Hospital in Kota Kinabalu, Sabah.