This is reduced victory is expected as young and middle-class voters send out a warning to a political dynasty which has ruled for nearly five decades.
Khama's Botswana Democratic Party (BDP), which has been in charge of the world's biggest diamond producer since independence from Britain in 1966, is credited with overseeing one of the most stable and democratic countries on a continent often tainted by conflict and corruption.
(READ MORE: Botswana works to diversify economy)
It also has the loyal support of a generation of voters won over with high spending on education and welfare benefits.
The sparsely populated country of 2 million has been one of the world's fastest growing economies since the 1970s and regularly comes near the top of African governance and transparency indicators.
"We are proud of the BDP. Look around the rest of Africa and tell me who has done better," said 70-year-old retired nurse Bernadette Bagwase, who arrived at 5 a.m. in a sleepy suburb of the capital Gaborone to vote in her eleventh election.
"Some of us are content with stability," Bagwase added, her elderly friends nodding in agreement as a pair of donkeys chewed grass outside the polling station.
There is, however, growing discontent among younger voters and the urban middle-class who say the BDP has become complacent and has run out of ideas, pointing to the 20 percent unemployment rate and a slowing economy reliant on diamonds.
(WATCH VIDEO: Diamonds are Botswana’s best friend)
"I've got a thirst for change. We need to change our economy; diamonds aren't forever," dental therapist Kogotso Entaile, 23, told Reuters after casting his ballot for the coalition opposition Umbrella for Democratic Change (UDC).
"What we're saying is: thanks BDP, we appreciate what you've done. It's time to move aside."
Khama has also been criticised personally for being an authoritarian, notably with the introduction of an unpopular 50 percent alcohol tax and the forced evictions of bushmen out of their traditional hunting grounds in the Kalahari Desert.
The 61-year-old president has said only the BDP is competent enough to rule and pledged to create jobs and improve water and electricity supply if he is given another term in office.
Last week Botswana's sole power station broke down, forcing it to rely on electricity from neighbouring South Africa.
About 824,000 people are expected to elect 57 lawmakers who will then choose the president. The BDP's stiffest opposition will come from the UDC and the Botswana Congress Party (BCP).