Calcium, an important secondary messenger, lies at the hub of multiple signaling pathways. The increase in cytosolic calcium contributed by different calcium-permeable channels can create transient high-calcium microenvironments and activate distinct signaling cascades in neurons. The spatio-temporal calcium changes, and calcium-mediated signaling pathways act as critical regulators of synaptic plasticity. Here, we have studied the regulation of activity-mediated protein synthesis by calcium response generated on NMDAR or mGluR stimulation in rat primary cortical neurons. Using calcium imaging, immunoblotting and immunostaining, we demonstrate that stimulation of NMDARs generates a protein synthesis response involving 3 phases - increased translation inhibition, followed by decrease in translation inhibition, and increased translation activation. Calcium influx through NMDARs elicits increased translation inhibition, which is necessary for the successive phases. Calcium through L-VGCCs acts as a switch from translation inhibition to the activation phase. NMDAR-mediated translation activation requires the contribution of L-VGCCs, Ryanodine receptors, and SOCE. Further, we show that IP3-mediated calcium release and SOCE are essential for mGluR-mediated translation upregulation. Finally, we show the relevance of our findings in the context of Alzheimer's disease. Using neurons derived from human fAD iPSCs and transgenic AD mice, we demonstrate the dysregulation of NMDAR mediated calcium and translation response. Our study highlights the complex interplay between calcium signaling and protein synthesis, and its implications in neurodegeneration.