COVID-19 pandemic has taught us the crucial role of immunity in children as well as in adults. It has also described a boosted expression of innate immune responses, increased expression of IFN-gamma in the upper airways to fight SARS-CoV-2 infection and an increase of T-regulatory chambers in children that determines the severity of disease expression among other factors. Although immune mechanisms seem to play a key role, experts are also considering the role of the endothelium. While initially considered to be a respiratory disease, evidence now suggests COVID-19 be a systemic inflammatory condition where the virus may invade nearly all the parts and cause endothelial inflammation. Endothelial phlogosis and activation of the coagulation cascade as determined by lab investigations are the hallmarks of the disease, with thromboembolic events and myocarditis as the consequences. Adults reported more thromboembolic events during or after COVID-19 than children. These events were rarely found in children during COVID-19, and if developed Multisystem Inflammatory Syndrome (MIS-C) after SARS-CoV-2 infection, high D-Dimers, myocardial dysfunction or coronary involvement, were promptly managed with anti-coagulants or anti-aggregants. Long COVID observes chronic inappropriate endothelial and platelet activation, lung hypoperfusion and micro clots. Evidence favour the pivotal role of the immune system and endothelial/coagulation pathways in the origin of Long COVID in a subgroup of patients. Further, myocarditis was also described in some young males as the primary complication of mRNA anti-COVID vaccination, indicating a close relationship with cells interfacing with the blood. These discrepancies in immune responses to vaccinations and infection are developing significantly inconsistent susceptibility to reinfections in people of all age groups.Various infectious diseases including COVID-19 and Long Covid have indicated a pivotal role of endothelial cells (ECs) and platelets in immune responses, chronic inflammation, and, perhaps, long-term outcomes in infections and other inflammatory diseases. Considering these together, these observations indicate the active and pivotal role of the endothelium in immunity, responses to infections, and homeostasis of the organisms.The recent data from COVID-19 and Long COVID showed the importance of anticoagulation and/or anti-aggregation approaches in improving outcomes in severe COVID-19 and improving symptoms in Long COVID patients. This further mandates focusing on ECs and platelets in infectious conditions and suggests that managing inflammation solely may not fully restore homeostasis in chronic inflammatory processes.Notably, there have been fewer studies in children investigating the function of ECs and platelets in modulating immune responses, but the current evidence from the adults’ demands undertaking such studies on priority. Future research must explore the role of platelets and ECs on blood clotting and vascular homeostasis along with investigating their complex involvement in immunity and as targets for future anti-inflammatory therapies.Buonsenso D. Childhood Immunity and Infections: Time to Consider Endothelial Cells and Platelets. Children. 2022; 9(6):841. https://doi.org/10.3390/children9060841