His long-time assistant Michael Cornandez was also killed.
It is believed that the accident took place at approximately 1am near 301.6 northbound marker along the the North-South Highway.
Malaysiakini learnt that Karpal and Ram, who is also a lawyer, were heading north for a court case later today.
Photos taken at the scene of the accident show the white Toyota Alphard badly damaged.
When contacted, a Ipoh police spokesperson told Malaysiakini that it is believed the MPV crashed into a lorry which switched lanes without indication.
Karpal, 74, became paralysed and wheelchair-bound after a car accident in 2005.
The vocal politician graduated from University of Singapore and started his law practice before running for Parliament in 1978.
His long tenure as Jelutong MP and fiery speeches in the Dewan Rakyat earned him the moniker "Tiger of Jelutong".
Karpal had recently relinquished his post as DAP chairperson pending the disposal of his appeal against a sedition charge.
Last month, the High Court found him guilty of uttering seditious words against the Sultan of Perak at the height of the constitutional crisis in 2009.
Meanwhile, Prime Minister Najib Abdul Razak conveyed his condolences via Twitter.
"I have just landed at Ankara when I heard the news that YB Karpal Singh died in a road accident. My condolences to the family," read the premier's tweet.
Other netizens also expressed condolences and shock over Karpal's passing.
"Shocked and sad news! DAP chairman Karpal Singh passed away in accident tonight. Malaysia has lost a truly patriotic son," wrote Taiping MP Nga Kor Ming.
"Our dear Mr Karpal is no longer with us... I just can't accept it...," said Kulai MP Teo Nie Ching.
Read more: http://www.malaysiakini.com/news/260226