Blood cells serve as a relevant source of bioactive substances that provide neuroprotection following stroke. Blood cells, as a cell source for secretome production, exhibit the potential to be stimulated by external stimuli, such as remote ischemic conditioning (RIC), resulting in changes to the quantitative and qualitative profile of released proteins, leading to an even higher potential to activate pro-survival mechanisms in ischemia-affected neurons. This reprogramming is characterized by attenuated blood cell hemolysis and enhanced oxidative defense mechanisms in the blood cells. Focusing on the paracrine activity, stimulation of blood cells tends to suppress rather than enhance the synthesis of protein released to the cell surrounding, while only minimal changes in the biomacromolecular composition of the secretome occur. This is reflected within the affected Gene Ontology (GO) terms, by the suppression of protein synthesis involved in immunomodulation, metabolic processes related to the antioxidant glutathione, and the loss of synaptic connections. Conversely, it also includes the downregulation of proteins that negatively regulate the extrinsic apoptotic signaling pathway. RIC-mediated protein synthesis/secretion reprogramming of blood cells mediates meaningful changes in the recipient of the secretome treatment, in enhanced survival of neurons, reduced redox imbalance, and extracellular content of the major neurotransmitter glutamate in the penumbra region and decreases the systemic oxidative stress index. Due to the easy accessibility of blood cell sources for its production, the secretome derived from properly primed cells represents a highly attractive strategy for stroke management—albeit currently limited to the experimental stage.