Teachers will encourage students to use "mind exercises" that train their attention on the present, such as deep breathing, in the Wellcome Trust study. Scientists say there is limited research to show mindfulness works.
The study will see teenagers fill in questionnaires about their mood to see if it does have an effect. Mindfulness is already taught in some schools, but in this first large-scale trial, researchers want to find out whether introducing mindfulness to teenagers early on could help build their psychological resilience.
The £6.4m programme will be carried out by teams at the University of Oxford, University College London and Medical Research Council over seven years.
William Kukyen, a professor of psychology at Oxford, says they are approaching the trial with an open mind. But he argues that adolescence could be a key time to intervene - research increasingly suggests mental illness often takes root before before the age of 15 and that the brain goes through an intense period of development during teenage years.
Sessions will include a practice known as "thought buses", where children are encouraged to think of their thoughts as buses that they can choose to board or let pass by. Others focus on deep breathing - for example, counting in for seven seconds and breathing out for 11.
In each case the aim is to focus attention on the here and now, to make students aware of impulsive behaviour, and - over time - improve their ability to solve problems when under stress.
Researchers plan to recruit about 6,000 children aged 11 to 14 in 76 schools. Half will be given 10 mindfulness sessions over a school term. The others, for comparison, will attend personal and social education classes as usual.
The trial, expected to begin late next year, will run for five years, including a follow-up period of two years for each student. A separate, smaller group will also have laboratory-based tests and brain scans.