A new Global Investment Framework for Women's and Children's Health demonstrates how investment in women's and children's health will secure high health, social, and economic returns. We costed health systems strengthening and six investment packages for: maternal and newborn health, child health, immunisation, family planning, HIV/AIDS, and malaria. Nutrition is a cross-cutting theme. We then used simulation modelling to estimate the health and socioeconomic returns of these investments. Increasing health expenditure by just $5 per person per year up to 2035 in 74 high-burden countries could yield up to nine times that value in economic and social benefits. These returns include greater gross domestic product (GDP) growth through improved productivity, and prevention of the needless deaths of 147 million children, 32 million stillbirths, and 5 million women by 2035. These gains could be achieved by an additional investment of $30 billion per year, equivalent to a 2% increase above current spending.