Introduction Sickle cell disease (SCD) is characterized by acute vaso-occlusive crisis (VOC) often manifested as painful episodes. Environmental factors are known to play a role in the frequency and severity of VOC. Methods The aim of this study is to analyze the relationship between weather changes and VOC in children with SCD. Data on daily temperature, humidity, and wind speed in Brooklyn, New York was collected over one year. Daily census data of children < 20 years of age with SCD presenting with VOC during the study period was retrieved from the Health Information Systems database. Data was analyzed to determine correlations of daily temperature, humidity, and wind speed with the number of VOCs using Pearson correlation co-efficient and time-series statistics. Results The total number of episodes of VOC was 344, with 218 outpatients and 126 inpatients. Total episodes of VOC peaked during January (n=44), while they were lowest in July (n=16). We observed a negative correlation of VOC with temperature (r= -0.05, p=0.04) and no correlation with humidity (r=0.01, p=0.85) was noted. Analysis of wind speed showed a negative correlation with VOC which is not significant. Conclusion No significant correlation was found between changes in humidity or wind speed and VOC. As this study was performed in an urban environment with extreme weather changes, results may be different in other geographic areas.