A high concentration of diverse macromolecules causes a densely packed environment, influencing both function and structural change of the cell organelles, cytoplasm, and molecules within. The concept of molecular crowding was for the first time introduced in the 70 s but was only accepted at the end of the 90 s. Crowding demonstrates how the high concentration of macromolecules, such as proteins, nucleic acids, and polysaccharides, influences the behavior and interactions of these molecules. This systematic review explored recent literature that impacted the understanding of molecular crowding, emphasizing the effects of molecular crowding on cytoplasm, nucleus, endoplasmic reticulum, Golgi apparatus, and chloroplasts. Numerous scientific literatures have confirmed that crowding impacts practically all aspects of these organelles' structure and functions, including gene expression regulation, protein folding, enzyme activity, and the organization of cellular structures like the cytoskeleton and chromatin, and consequently clearly affects the regulation of cell metabolic activities. Moderate macromolecular crowding contributes to the normal functioning of these cellular processes, however excessive crowding triggers various responses, disrupts the normal functioning of the cell, and can result in various diseases, ranging from neurodegenerative disorders to diabetes. Different therapeutic options are being explored to help mitigate the negative effects of excessive macromolecular crowding and prevent disease development.