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Eukaryotic cytosolic protein synthesis typically begins with methionine (Met), but formyl-methionine (fMet) can also be incorporated. However, the mechanism regulating fMet incorporation and preventing potential toxicity remains unclear. This study reveals that the fMet-mediated ribosome quality control (fMet-RQC) pathway in Saccharomyces cerevisiae plays a crucial role in maintaining translation fidelity. Nip1, a subunit of eukaryotic translation initiation factor 3, recognizes N-terminal fMet in nascent polypeptides and recruits Arf1, leading to ribosome stalling and dissociation. This prevents the accumulation of toxic fMet-polypeptides, which can disrupt N-terminal Met modifications and aggregate with ribosomes. Notably, loss of the fMet-RQC pathway impairs stress granule formation and increases sensitivity to cold stress. These findings suggest that regulating fMet incorporation and clearance is essential for maintaining cellular homeostasis and adapting to environmental stress.