At least 54 children, most aged under three, have died from the disease since mid-April, out of 61 cases, according to the latest update from the World Health Organization (WHO).
The school closure, which affects tens of thousands of pupils, also aims to ease parents' fears about the outbreak, said Mak Vann, secretary of state at Cambodia's education ministry.
"This is to prevent the spread of the disease," he told AFP. "Parents have voiced concern that the disease could infect their children."
The illness and its high fatality rate initially stumped health experts in Cambodia, but the WHO said last week most victims tested positive for Enterovirus 71 (EV-71), which causes a lethal strain of hand, foot and mouth disease and is fairly common in Asia.
The UN health body also found the use of steroids as part of the treatment had been shown to worsen the condition of patients with EV-71, whose symptoms include high fever and respiratory problems.
In neighbouring Thailand, 22 schools in the capital had closed after fears of an outbreak, but by Wednesday all but three of those had re-opened, according to Bangkok authorities.
Hand, foot and mouth disease is contagious and spreads through direct contact with the bodily fluids or faeces of an infected person. Experts say good hygiene is the best form of prevention.