Innate immune cells are capable of polarizing to a range of effector functions including oxidative stress, antigen presentation, phagocytosis and cytokine secretion. However, how innate immune cells respond to extrinsic signals and whether unique polarization signatures govern their effector functions remains poorly understood. Here we report the ligand-selective transcriptome and phosphoproteome of innate immune cells by single-cell RNA-seq (scRNA-seq) and quantitative mass spectrometry. Innate immune cells exhibit unique polarization profiles upon ligand-selective activation induced by extrinsic molecular signals fibrin, complement, and LPS. While complement and LPS induced host defense and classical inflammatory states, respectively, fibrin induced prooxidant innate immune activation similar to the oxidative stress signature in neuroinflammatory disease. Thus, ligand-selective activation of innate immunity may be a key contributor of niche-specific polarization with implications for selective therapeutic targeting of pathogenic innate immune cells. This comprehensive dataset provides a resource for further investigation of innate immune cell functions in health and disease.