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Background and Purpose: The diagnosis of cardioembolic stroke can be challenging for patient management in secondary stroke prevention, particularly in the case of covert paroxysmal atrial fibrillation. The molecular composition of a cerebral thrombus is related to its origin. Therefore, proteomic and metabolomic analyses of the retrieved thrombotic material should allow the identification of biomarkers or signatures to improve the etiological diagnosis of stroke. Methods: In this pilot study, the proteome and metabolome of cerebral thrombi from atherothrombotic and cardioembolic stroke patients were studied according to ASCOD phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes; D: dissection), with the highest causality grade, from the ThrombiOMIC cohort (consecutive patients with stroke recanalized by mechanical thrombectomy in an acute phase). Proteomic and metabolomic results were used separately or combined, and the obtained omic signatures were compared with classical cardioembolic stroke predictors using pairwise comparisons of the area under receiver operating characteristics. Results: Among 59 patients of the ThrombiOMIC cohort, 34 patients with stroke showed a cardioembolic phenotype and 7 had an atherothrombotic phenotype. Two thousand four hundred fifty-six proteins and 5019 molecular features of the cerebral thrombi were identified using untargeted proteomic and metabolomic approaches, respectively. Area under receiver operating characteristics to predict the cardioembolic origin of stroke were calculated using the proteomic results (0.945 [95% CI, 0.871–1]), the metabolomic results (0.836 [95% CI, 0.714–0.958]), and combined signatures (0.996 [95% CI, 0.984–1]). The diagnostic performance of the combined signatures was significantly higher than that of classical predictors such as the plasmatic BNP (B-type natriuretic peptide) level (area under receiver operating characteristics, 0.803 [95% CI, 0.629–0.976]). Conclusions: The combined proteomic and metabolomic analyses of retrieved cerebral thrombi is a very promising molecular approach to predict the cardioembolic cause of stroke and to improve secondary stroke prevention strategies.