Data analytics with Machine Learning (ML) using physics knowledge and big data offers high potential to continuously transform raw data to newfound knowledge of Process-Structure-Property (PSP) causal relationships. In Additive Manufacturing (AM), however, realizing the potential is still limited largely due to the lack of a systematic way to learn the PSP relationships for various AM processes. To address the limitation, this paper proposes a novel framework driven by physics-guided ML, which consists of three tiers: (1) knowledge of predictive PSP models and physics, (2) PSP features of interest, and (3) raw AM data. The framework defines a PSP-learning process with two sub-processes. The first uses a knowledge-graph-guided top-down approach to generate the requirements for predictive analytics and data acquisition. The second uses a data-driven bottom-up approach to construct and model new PSP knowledge. Together, these processes connect the proposed framework to decision-making and control activities and physical and virtual AM systems, respectively. The paper includes a case study based on Laser Powder Bed Fusion processes including AM Metrology Testbed at the National Institute of Standards and Technology (NIST). The case study introduces predictive ML models and PSP knowledge extracted from the models. We also demonstrate the framework using an ML-Integrated Knowledge Extraction module called MIKE in NIST’s collaborative AM Material Database. The framework newly enables a systematic physics-guided data-driven approach for PSP in AM that can couple physics knowledge with the versatility of data-driven ML models. Using the approach, the framework continuously updates the models (1) to improve the understanding of dynamically generated AM data and (2) to link sub-models into coupled PSP models. Based on the improved understanding, the framework also facilitates decision-making and control activities for AM at multiple scales.