Full thickness thoraco-abdominal defects are traditionally challenging to reconstruct, exposing the patient to a significant risk of wound complications and functional impairment. The authors present an extremely challenging and unique case where a huge lateral thoraco-abdominal defect was reconstructed with a combination of innervated flaps allowing to completely restore contour and function of the operated region. A 77-year-old male patient presented with a leiomyosarcoma arising in the right lateral thoraco-abdominal region. Full-thickness resection involved the anterior part of the latissimus dorsi (LD) and serratus anterior muscles along with IX to XII ribs, a cuff of diaphragm muscle and the entire lateral abdominal wall, creating a 30 × 25 cm defect with exposure of right lung, liver, and ascending and transverse colon. After the placement of a synthetic mesh, a 28 × 16 cm pedicled innervated LD flap was advanced in V-Y fashion to cover the thoracic part of the defect. Then the patient was turned supine and a vastus lateralis free functional muscle transfer (FFMT) from the contralateral thigh was used to reconstruct the abdominal part of the defect. The recipient vessels were provided transposing the ipsilateral deep inferior epigastric pedicle according to the extra-anatomical pedicle rerouting technique. Motor branch for the VL was coapted to a sizeable intercostal nerve. The muscle was covered with split-thickness skin grafts. Both flaps healed uneventfully, allowing to obtain a complete restoration of form and function with M5 score according to the MRC Scale for muscle strength 8 months after surgery. Functional reconstruction of the lateral abdominal wall with FFMT has never been reported. Our successful case shows the importance of functional reconstruction of lateral thoraco-abdominal defects to prevent abdominal weakness or herniation, trunk instability, postural deficiencies and core strength loss.