Objective Methylphenidate is effective in reducing ADHD symptoms in the short term, but long-term benefits are inconsistent, possibly due to the development of tolerance. Moreover, little is known about its sustained effects on brain functional connectivity. We examined whether a 4-month methylphenidate treatment leads to sustained alterations in resting-state functional connectivity, and whether acute brain responses to methylphenidate decrease after treatment, as a potential marker of neurobiological tolerance. Method This is a secondary analysis of the ePOD-MPH RCT in which 50 boys and 49 men with ADHD were randomized to methylphenidate or placebo. Resting-state fMRI data were collected before, and one week after, a 4-month treatment period. At both visits, participants were scanned before and after an acute oral methylphenidate challenge. We computed whole-brain and default mode network (DMN) global efficiency, and DMN–whole-brain connectivity strength. Results In adults, methylphenidate (but not placebo) led to sustained increases in whole-brain efficiency (p=0.01) and DMN–whole-brain connectivity strength (p=0.03). No significant effects were observed in children (all p>0.17). Exploratory analyses indicated that whole-brain efficiency increases related to decreasing cognitive performance in methylphenidate-treated children, but improving performance in placebo-treated children, suggesting treatment-dependent moderation (p<0.01). Acute connectivity responses remained stable in adults across visits (all p>0.15), but increased in children, regardless of treatment (all p<0.04). Conclusion Four months of methylphenidate treatment led to sustained functional connectivity changes in adults with ADHD, without evidence of neurobiological tolerance. These findings emphasize the importance of studying longer treatment durations, considering that methylphenidate treatments typically span multiple years.