Palani Digambaram and V Radhakrishnan, both deputy ministers from parties representing Tamils of Indian-origin, said they were leaving the government to side with the opposition unity candidate Maithripala Sirisena.
Rajapaksa is seeking a record-third term after announcing snap polls set for January 8.
Rajapaksa's ruling United People's Freedom Alliance coalition had 161 seats in the 225-member assembly. The tally now stands at 149, a seat below the two-thirds parliamentary majority.
Since calling the election, the Sri Lankan president has suffered a loss of 13 defections so far, including five Cabinet ministers and three deputy ministers.
Rajapaksa, however, has been able to gain the support of the main opposition United National Party's senior leader Tissa Attanayake who joined him on Monday.
Attanayake was unhappy with the UNP decision to back a unity candidate to challenge Rajapaksa.
Rajapaksa's defectors are led by his former Health Minister Sirisena who is the opposition unity candidate.
Sirisena, who was a senior minister in the ruling coalition, defected to the opposition camp along with several other senior leaders of the ruling UPFA coalition last month.
The two-thirds majority in Parliament had enabled Rajapaksa to lift the two-term bar on contesting for the presidency. The opposition have announced a plan for democratic reforms calling Rajapaksa's administration authoritarian and family-centric.
The opposition unity candidate has pledged to abolish the system of executive presidency by forming a national unity government.
Rajapaksa called the election two years ahead of schedule in an apparent attempt to seek a fresh mandate before his party's popularity tumbles further, after dropping over 21 percent in September's local elections.