However, the main contest will be between the ruling AIADMK, principle opposition party DMK, and an Independent legislator-floated AMMK party.
Actor-politician Kamal Haasan's party Makkal Needhi Maiam (MNM) candidates are also in the contention.
By-elections for 18 Assembly constituencies were held on April 18 along with the Lok Sabha polls in the state.
While the parties traded charges and counter charges during their campaigning for the May 19 by-elections, Haasan towards the end created a nationwide row with his Hindu terrorist remark.
On Sunday, at the Aravakuruchi Assembly constituency, Haasan, while campaigning for his party candidate, said about the killer of Mahatma Gandhi "The first extremist of independent India was a Hindu - Nathuram Godse. It all started from there."
The statement drew angry responses from the Bharatiya Janata Party (BJP) and the AIADMK.
Haasan has applied for anticipatory bail as a case has been registered against him in the Aravakuruchi police station.
Political analyst Raveendhran Dhuraiswamy told IANS that the two stage by-elections for the 22 Assembly seats is advantageous for the ruling AIADMK and also for Dhinakaran's AMMK.
According to analysts, the AIADMK may not find it difficult to win eight seats out of the 22 to continue in power.
In the 234 member Tamil Nadu Assembly, the ruling AIADMK has 113 members (including the Speaker), DMK 88, Congress 8, IUML and Independent one each.
To attain a simple majority, the AIADMK has to win just five seats in the by-elections. In order to be safe against switching of camps by some of the lawmakers, the AIADMK has to win seven or eight seats.
Interestingly, three AIADMK legislators were issued show cause notices by Speaker P.Dhanapal as the ruling party felt that they were moving towards Dhinakaran.
However, the Supreme Court has stayed the disqualification proceedings against the three lawmakers.
On the other hand, the DMK (88 members) has to win all the 22 seats to take the tally along with its allies -- Congress (eight members) and IUML (one member) -- to 119, just one number over the simple majority.
DMK President M.K. Stalin said that along with the change in the Central government after May 23 - the day on which the Lok Sabha and by-election results will be declared -- there will be a change of government in Tamil Nadu.
One interesting factor in this situation will be the election result for the Kanyakumari Lok Sabha seat. The Congress party's H. Vasanthakumar, representing the Nanguneri Assembly constituency, is contesting in the Lok Sabha polls from Kanyakumari constituency.
It will be interesting to see whether he would retain the Assembly membership or opt for Lok Sabha membership if he wins in the Lok Sabha polls.
"It will be an acid test for Stalin's leadership. Assuming Dhinakaran's AMMK wins some seats, what action Stalin will take will have to be seen," Dhuraiswamy had told IANS earlier.
It has to be seen whether the AMMK will join hands with the DMK combine to topple the AIADMK government.
"If the BJP retains power at the Centre and the political situation in Tamil Nadu turns fluid then the former can suspend the Assembly for sometime to stall the DMK," political commentator Maalan Narayanan told IANS.