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.
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.
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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 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 per cent in September's local elections.