Increased interest in luminescent nanoparticles has made it possible to identify the feasibility of developing novel materials or improving existing materials, including designing materials at the nanoscale that can be easily controlled and have broad applications. In this study, we design and synthesize quantum dots (QDs), a type of semiconducting nanocrystals that fluoresce under UV light and have been extensively applied in optoelectronics, chemosensing, biotechnology, and biomedicine. Here, the relative quantum yield (QY) was correlated with the synthesis variables and nanoparticle architecture: core composition, ligand type, molar ratio, reaction time, and shell type. Obtained QDs were characterized using UV-Vis, IR, fluorescence, XRD, and TEM techniques. The investigated nanostructures had QYs between 15 and 68%, long-term stability, and monolayers with thicknesses of approximately 0.3 nm. A computational study on small CdTe clusters was performed to evaluate the effect of ligands on QY; the effects of the geometry, the gap between the HUMO and LUMO, and binding energy on the cluster stability were also analyzed. Aqueous-phase synthesis was shown to be an excellent alternative for fabricating high-fluorescence and stable QDs useful in future applications like chemo/biosensing and bioimaging.