Isocyanate blocking can improve the long-term stability of isocyanate and reduce its toxicity for use in aqueous systems. The current isocyanate blocking technique has a low blocking degree, and this study designed a reasonable process route using tetrabutylammonium bromide (TBAB) as the phase transfer catalyst in isopropyl alcohol (IPA) solvent to prepare water-soluble isophorone diisocyanate (IPDI) blocked by NaHSO3 with a blocking degree of ≥ 98%. This work used 1% m (TBAB) / m (NaHSO3) with a m (IPA): m (H2O) ratio of 1 : 1; the NaHSO3 was prepared in a 15% aqueous solution. The n (HSO3−) : n (-NCO) ratio was greater than 1 : 1. The stirring speed was 200 r/min, the reaction temperature was 30 °C, and the reaction time was 2.5 h. FT-IR was used to analyze the changes in the main functional groups during the blocking reaction. TG and DCS were used to analyze the deblocking characteristics of water-soluble blocked IPDI. This paper also studied the effect of the blocked IPDI on paper properties. Experimental results showed that the strength and water resistance of paper made from the treated fiber can be remarkably improved by using water-soluble blocked IPDI.