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The protein lysine methyltransferase, SMYD2 is involved in diverse cellular events by regulating protein functions through lysine methylation. Though several substrate proteins of SMYD2 are well-studied, only a limited number of its interaction partners have been identified and characterized. Here, we performed a yeast two-hybrid screening of SMYD2 and found that the ribosomal protein, eL21 could interact with SMYD2. SMYD2-eL21 interaction in the human cells was confirmed by immunoprecipitation methods. In vitro pull-down assays revealed that SMYD2 interacts with eL21 directly through its SET and MYND domain. Computational mapping, followed by experimental studies identified that Lys81 and Lys83 residues of eL21 are important for the SMYD2-eL21 interaction. Evolutionary analysis showed that these residues might have co-evolved with the emergence of SMYD2. We found that eL21 regulates the steady state levels of SMYD2 by promoting its transcription and inhibiting its proteasomal degradation. Importantly, SMYD2-eL21 interaction plays an important role in regulating cell proliferation and its dysregulation might lead to tumorigenesis. Our findings highlight a novel extra-ribosomal function of eL21 on regulating SMYD2 levels and imply that ribosomal proteins might regulate wide range of cellular functions through protein-protein interactions in addition to their core function in translation., (Copyright © 2021 Elsevier B.V. All rights reserved.)