Abstract Background Suicide is a major public health challenge globally and specifically in India where 36.6% and 24.3% of all suicides worldwide occur in women and men, respectively. The United Nations Sustainable Development Goals uses suicide rate as one of two indicators for Target 3.4, aimed at reducing these deaths by one third by 2030. India has no examples of large-scale implementation of evidence-based interventions to prevent suicide; however, there is a sizeable evidence base to draw on for suicide prevention strategies that have been piloted in India or proven to be effective regionally or internationally. Method The SPIRIT study is designed as a cluster-randomized superiority trial and uses mixed methods to evaluate the implementation, effectiveness and costs of an integrated suicide prevention programme consisting of three integrated interventions including (1) a secondary-school-based intervention to reduce suicidal ideation among adolescents, (2) a community storage facility intervention to reduce access to pesticides and (3) training for community health workers in recognition, management, and appropriate referral of people identified with high suicidal risk. Discussion Combining three evidence-based interventions that tackle suicide among high-risk groups may generate a synergistic impact in reducing suicides at the community level in rural areas in India. Examination of implementation processes throughout the trial will also help to prepare a roadmap for policymakers and researchers looking to implement suicide prevention interventions in other countries and at scale. Trial registration Clinical Trial Registry of Indian Council of Medical Research, India: CTRI/2017/04/008313. Registered on 7 April 2017. http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=18256&EncHid=&userName=SPIRIT Trial registry was last modified on 28 June 2019.