The intracellular protein constantly remains in the dynamic process of synthesis and degradation, and its homeostasis appears to be closely related to the cellular function. A variety of protein quality control (PQC) mechanisms exist to monitor abnormalities occurred during protein synthesis and degradation, thereby ensuring proteome integrity and cellular fitness. The ribosome is the most abundant organelle in cells, and it is the major site for protein synthesis, for which each stage from biosynthesis to degradation is tightly controlled by various quality control mechanisms. Ribosome-associated quality control (RQC) and ribophagy are identified as two major ribosome-associated PQC mechanisms that synergistically involve in the maintenance of translational function and protein homeostasis. Also, they represent key players in adjusting ribosome content and translational activity for the changing environment, in turn facilitating cell survival under stress conditions. The dysregulation of RQC and ribophagy malfunction can substantially alter cellular fate and render cell death, resulting in the onset and development of various ribosomopathies, including congenital diseases, neurological diseases, and malignant tumors. Targeting ribosomal dysfunction by restoring effective ribosome-associated PQC may serve as potential remedy in treating ribosomopathies. The current review focuses on ribosomal-associated PQC with in-depth discussion regarding to the key roles of these pathways for the maintenance of protein homeostasis as well as their potential effects on the development of various human diseases.