Quantum entanglement is commonly assumed to be a central resource for quantum computing and quantum simulation. Nonetheless, the capability to detect it in many-body systems is severely limited by the absence of sufficiently scalable and flexible certification tools. This issue is particularly critical in situations where the structure of entanglement is a priori unknown, and where one cannot rely on existing entanglement witnesses. Here, we implement a scheme in which the knowledge of the mean value of arbitrary observables can be used to probe multipartite entanglement in a scalable, certified, and systematic manner. Specifically, we rely on positive semidefinite conditions, independent of partial-transposition-based criteria, necessarily obeyed if the data can be reproduced by a separable state. The violation of any of these conditions yields a specific entanglement witness, tailored to the data of interest, revealing the salient features of the data which are impossible to reproduce without entanglement. We validate this approach by probing theoretical many-body states of several hundreds of qubits relevant to existing experiments: a single-particle quench in a one-dimensional XX chain; a many-body quench in a two-dimensional XX model with 1/r3 interactions; and thermal equilibrium states of Heisenberg and transverse-field Ising chains. In all cases, these investigations have led us to discover new entanglement witnesses, some of which could be characterized analytically, generalizing existing results in the literature. In summary, our paper introduces a flexible data-driven entanglement detection technique for uncharacterized quantum many-body states, of immediate relevance to experiments in a quantum advantage regime.Received 11 August 2021Revised 2 December 2021Accepted 22 February 2022DOI:https://doi.org/10.1103/PRXQuantum.3.010342Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.Published by the American Physical SocietyPhysics Subject Headings (PhySH)Research AreasEntanglement detectionQuantum entanglementPhysical SystemsQuantum spin modelsTechniquesData analysisSemiclassical methodsQuantum InformationAtomic, Molecular & OpticalStatistical Physics