Nanofibrillar cellulose (NFC)-derived dressings such as films, hydrogels, and aerogels are one of the favorable materials for wound healing due to their proper mechanical properties and water holding ability. However, the therapeutic differences between native and anionic NFC materials are rarely studied. In this report, we compared the differences and addressed the regenerative potential of native and anionic wood-derived NFC hydrogels for wound treatment. In vitro characteristics of the hydrogels were detected using scanning electron microscopy, rheological measurements, and swelling and hemolytic activity assays. Skin regeneration at an early stage after hydrogel treatment was analyzed using an in vivo splinted excisional full-thickness skin wound model in C57BL/6 mice. Both native NFC and anionic NFC (ANFC) hydrogel with differing mechanical and surface properties were shown to be biocompatible. Surprisingly, wounds treated with NFC and ANFC hydrogel did not show any statistical difference compared with control wounds and progressed through normal wound closure, inflammatory response, re-epithelialization, vascularization, and tissue maturation with no signs of fibrosis. The data show here for the first time the therapeutic performance of native and anionic NFC hydrogel in a wound mimicking human wound healing mechanisms. The mechanical properties of native and anionic NFC hydrogels such as the capability to modify material stiffness may also prove to be valuable in the management of wounds in the future.