With the fast development of multi‐dimensional data compression and pattern classification techniques, vector quantization (VQ) has become a system that allows large reduction of data storage and computational effort. One of the most recent VQ techniques that handle the poor estimation of vector centroids due to biased data from undersampling is to use fuzzy declustering‐based vector quantization (FDVQ) technique. Therefore, in this paper, we are motivated to propose a justification of FDVQ based hidden Markov model (HMM) for investigating its effectiveness and efficiency in classification of genotype‐image phenotypes. The performance evaluation and comparison of the recognition accuracy between a proposed FDVQ based HMM (FDVQ‐HMM) and a well‐known LBG (Linde, Buzo, Gray) vector quantization based HMM (LBG‐HMM) will be carried out. The experimental results show that the performances of both FDVQ‐HMM and LBG‐HMM are almost similar. Finally, we have justified the competitiveness of FDVQ‐HMM in classification of cellular phenotype image database by using hypotheses t‐test. As a result, we have validated that the FDVQ algorithm is a robust and an efficient classification technique in the application of RNAi genome‐wide screening image data.