Background Currently, there are no reliable clinical tools available for predicting asthma in pre-school-aged children with recurrent wheezing. The aim of this study was to evaluate the usefulness of serum periostin, YKL-40, and osteopontin biomarkers in wheezy pre-school-aged children for predicting the development of asthma in school ages. Methods The study was prospectively conducted between 2011 and 2017. The clinical features of the pre-school-aged children with recurrent wheezing and the levels of serum periostin, YKL-40, and osteopontin were measured. The same participants were reevaluated in school-age period, and participants with asthma were identified. Relative risk (RR) for the development of asthma was analyzed. Results Of the 197 pre-school-aged children with recurrent wheezing who were reevaluated in school-age years, 32% of them had asthma. Serum periostin, YKL-40, and osteopontin levels at admission could not predict participants who would have asthma symptoms in school-age years. The RR for continuing of asthma symptoms was higher in participants who had their first wheezing episode before 1 year of age, preterm birth, cesarean section delivery, prenatal smoking exposure, multi-trigger wheezing, parental asthma, modified asthma predictive index positivity, prophylactic vitamin D intake <= 12 months, breastfeeding time <= 12 month, and aeroallergen sensitivity [RR (95% CI) and P value: 2.813 (1.299-6.091), 0.002; 1.972 (1.274-3.052), 0.009; 1.929 (1.195-3.114), 0.004; 2.232 (1.463-3.406), <0.001; 3.152 (1.949-5.097), <0.001; 1.730 (1.144-2.615), 0.016; 2.427 (1.559-3.777), <0.001; 2.955 (1.558-5.604), <0.001; 1.767 (1.084-2.881), 0.016; 0.765 (0.556-1.053), 0.016; respectively]. Conclusion Results have shown that clinical features were more valuable than biomarkers in predicting having asthma in school-age years in participants who had recurrent wheezing in pre-school-age period.