Number sense is believed to be critical for math development. It is putatively an implicitly learned skill and may therefore have limitations in terms of being explicitly trained, particularly in individuals with altered neurodevelopment. A case series study was conducted using an adaptive, computerised programme that focused on number sense and general problem-solving skills. The study was designed to investigate training effects on performance as well as brain function in a group of children with Turner syndrome who are at risk for math difficulties and altered development of math-related brain networks. Standardised measurements of math and math-related cognitive skills as well as functional magnetic resonance imaging (fMRI) were used to assess behavioural and neurobiological outcomes following training. Participants demonstrated significantly increased basic math skills, including number sense, and calculation as well as processing speed, cognitive flexibility and visual-spatial processing skills. With the exception of calculation, increased scores also were clinically significant (i.e., recovered) based on reliable change analysis. Participants additionally demonstrated significantly increased bilateral parietal lobe activation and decreased frontal-striatal and mesial temporal activation following the training programme. These findings show proof of concept for an accessible training approach that may be potentially associated with improved number sense, math and related skills, as well as functional changes in math-related neural systems, even among individuals at risk for altered brain development.