Opposition leader Lazarus Chakwera had 35.44 per cent, while Vice President Saulos Chilima was on 18 per cent, according to the partial results.
Mutharika, 78, campaigned for a second five-year term on his record of improving Malawi's scant road and power infrastructure.
But his government has been dogged by several high-profile cases of corruption and nepotism.
Chakwera on Wednesday warned of alleged attempts to rig Tuesday's election, saying his Malawi Congress Party (MCP) was conducting its own count that showed he was ahead.
The southeastern African country has around 6.8 million potential voters, with more than half aged under 35. Turnout data has not been published.