Voting booths in the kingdom's 400 constituencies will open at 8am (0100 GMT) and close at 3pm with projected unofficial results by television stations expected later in the day.
Thaksin has vowed to try to govern without having to form a coalition in his second term.
"We want to be a single-party government," he told a cheering crowd in Bangkok at his last rally on Friday, distancing himself from coalition partner party Chart Thai.
The premier won a landslide victory in February 2001 and is shooting for his party to win at least 350 seats out of the 500 up for grabs when the kingdom's 44 million eligible voters hit the ballot boxes.
In addition to 400 constituency seats, there are 100 at-large candidates chosen by their party following a proportional representation system.
Thaksin has waged a war against
drug lords in Thailand
Thaksin's critics fear that if Thai Rak Thai scoops the 350 seats it is aiming for, parliament will lose its ability to check his government's grip on power.
In a country where every previous elected government has fallen either to military coups or political squabbling, Thaksin's is the first to survive a full four-year term.
The telecoms mogul has largely delivered on his promises to revive Thailand's fortunes after the 1997 Asian financial crisis.
And despite accusations over his authoritarian style, Thaksin has proved a popular leader.
Pre-election polls are officially banned, but a survey by the respected Matichon newspaper and Dsurakitvanid University predicted that TRT would win 349 seats, up from its present share of 320.
The prospect of an even more powerful Thaksin raises alarms among groups such as Human Rights Watch, which now considers Thailand "a country of high concern".
Critics cite particular concern over Thaksin's military crackdown on a 13-month insurgency in Thailand's southernmost provinces, which has left more than 580 dead and sparked two controversial clashes that ended with the deaths of hundreds of protesters.
Thaksin's war on drugs left about 2275 suspected drug offenders dead in apparent extrajudicial killings between February and May 2003.