Energy efficiency measures and Industry 4.0 investments are prominent drivers of business competitiveness and sustainability, working toward sustainable development goals and decarbonization commitments. We analyzed data from a survey of 239 Italian manufacturing firms conducted in 2021. The survey was designed to identify drivers of energy efficiency measures and Industry 4.0 measures, as well as barriers to their implementation. We also examined interventions on key business variables such as business model sustainability, corporate social responsibility, business economics, public image, reputation, and market positioning. Energy efficiency intervention drivers are correlated with sustainable corporate social responsibility and cost reduction, whereas Industry 4.0 intervention drivers are associated with production optimization variables. Prominent barriers to energy efficiency interventions relate to economic feasibility, regulatory uncertainty, and financial issues. Similarly, key barriers to Industry 4.0 interventions are economic feasibility, enabling infrastructures, and regulatory uncertainty. The implication of energy efficiency measures and Industry 4.0 investments are discussed to pave the way for complementarity, overlap, and contrasting effects of measures. The paper has business implications given that it benefits decision-makers to reduce the risk of strategic drift and increases the probability of meeting sustainable development goals and decarbonization targets of Sustainable Development Goal 11.