Background: Split-thickness skin grafting (STSG) is a frequently used reconstructive technique, and its donor site represents a standardized clinical model to evaluate wound dressings. We compared hydroactive nanocellulose-based, silver-impregnated and ibuprofen-containing foam wound dressings. Methods: A total of 46 patients scheduled for elective surgery were evaluated on the STSG donor site for wound healing (time-to-healing, Hollander Wound Evaluation Scale), pain level (Visual Analogue Scale), and handling (ease of use), as well as scar quality (Patient Scar Assessment Scale, Vancouver Scar Scale) after 3, 6 and 12 months. Results: Almost all dressings compared equally well. We observed statistically relevant differences for pain level favoring the ibuprofen-containing dressing (p = 0.002, ΔAIC = 8.1), and user friendliness in favor of nanocellulose (dressing removal: p = 0.037, ΔAIC = 2.59; application on patient: p = 0.042, ΔAIC = 2.33; wound adhesion: p = 0.017, ΔAIC = 4.16; sensation on skin: p = 0.027, ΔAIC = 3.21). We did not observe any differences for wound healing across all groups. Treatment with hydroactive nanocellulose and the ibuprofen-containing foam revealed statistically relevant better scar appearances as compared to the silver wound dressing (p < 0.001, ΔAIC = 14.77). Conclusion: All wound dressings performed equally well, with the detected statistical differences hinting future directions of clinical relevance. These include the reserved use of silver containing dressings for contaminated or close to contaminated wounds, and the facilitated clinical application of the nanocellulose dressing, which was the only suitable candidate in this series to be impregnated with a range of additional therapeutic agents (e.g., disinfectants and pain-modulating drugs). Personalized donor site management with the tested dressings can meet individual clinical requirements after STSG and improve management strategies and ultimately patient outcomes.