The KCNH2 gene-encoded KV11.1 voltage-gated potassium channel, also known as hERG, is abundantly expressed in the heart and brain, and plays an essential role in stabilizing cardiac and neuronal membrane potentials. Loss-of-function KCNH2 mutations, as well as pharmacological suppressions of human KV11.1 channel function, have been associated with arrhythmia and epilepsy. The majority of disease-related mutations involve aberrant KV11.1 protein folding, resulting in enhanced endoplasmic reticulum (ER)-associated degradation and decreased cell-surface protein level. Despite previous identification of several KV11.1-interacting E3 ubiquitin ligases and molecular chaperones, the molecular mechanisms governing KV11.1 protein quality at the ER are not well understood. Herein we aim to study KV11.1 protein quality control by the E3 ubiquitin ligase MKRN1. As supported by our co-immunoprecipitation and immunofluorescence data, MKRN1 appeared to preferentially interact with the amino-terminal region of immature KV11.1 protein at the ER. Further biochemical analyses suggested that MKRN1 promoted ubiquitination and ultimately proteasomal degradation of both wild-type and disease-related KV11.1. Collectively, our findings indicate that MKRN1 may contribute to early-stage ER protein quality control of the KV11.1 potassium channel in cardiac and neuronal cells.