This study investigated patterns of motor brain activation, white matter (WM) integrity of inter- and intrahemispheric connectivity and their associations with hand function in children with unilateral cerebral palsy (CP-U). Fourteen CP-U (mean age 10.6 ± 2.7 years) and 14 typically developing children (TDC) underwent magnetic resonance imaging. CP-U underwent extensive motor evaluation. Pattern of brain activation during a motor task was studied in 12 CP-U and six TDC, by calculating laterality index (LI) and percent activation in the sensorimotor areas (around the central sulcus), and quantifying the activation in the supplementary motor area (SMA). Diffusivity parameters were measured in CP-U and eight other TDC for the corpus callosum (CC), affected and less affected cortico-spinal tracts (CST), and posterior limb of the internal capsule (PLIC). Abnormal patterns of brain activation were detected in areas around the central sulcus in 9/12 CP-U, with bilateral activation and/or reduced percent activation. More activation in areas around the central sulcus of the affected hemisphere was associated with better hand function. CP-U demonstrated more activation in the SMA when moving the affected hand compared to the less affected hand. CP-U displayed reduced WM integrity compared to TDC, in the midbody and splenium of the CC, affected CST and affected PLIC. WM integrity in these tracts was correlated with hand function. While abnormal pattern of brain activation was detected mainly when moving the affected hand, the integrity of the CC was correlated with function of both hands and bimanual skills. This study highlights the importance of interhemispheric connectivity for hand function in CP-U, which may have clinical implications regarding prognosis and management.