Natural aging (NA) is unavoidable in Al-Mg-Si alloys during actual manufacturing. Revealing the reasons for the alloy strength reduction caused by the negative NA effect is of great significance to research and practice. In this work, atom probe tomography (APT) and transmission electron microscopy (TEM) were employed simultaneously to study the effect of NA on precipitates and their contributions to the strength of Al-Mg-Si alloys. It was found that the numerous clusters formed after significant NA are unstable and will dissolve into the matrix during initial AA. However, a few stable clusters are undissolved and will result in abnormal growth of β″, which then transforms to β′. Due to the decrease of nucleation sites resulting from the abnormal growth of precipitates, more solute atoms remain in the matrix. The calculation results show that the strengthening of the solid solution atoms is much smaller than that of large-sized β′, which is much less than that of fine β″. Therefore, lengthy NA causes a significant reduction in AA strength of the Al-Mg-Si alloy.