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The current work focuses on the formulation development, optimization, and in vivo assessment of nano-sized silver sulfadiazine (nSSD) and micron-sized silver sulfadiazine (mSSD) topical gel composed of Aloe vera gel (Aloe gel) and Carbopol 940 for the management of second-degree burn wound. The optimized concentration of gel-forming agent (Carbopol 940) was chosen based on best possible consistency and spreadability of the gel. The second-degree burn infliction was developed in the posterior region of rats followed by anesthesia. Afterward, the created wounds were further treated individually by both the gel formulation (1 application daily) for 14 days and observations were recorded. The nSSD gel showed better wound healing and a higher degree of tissue hyperplasia as compared with mSSD gel in rats. In vitro drug release study showed better drug release from nSSD gel (74.25 ± 3.331%) as compared with mSSD gel formulation (61.32 ± 2.112%) after 24 hours. The nSSD and mSSD topical gel-treated rats showed 95.63% and 78.75% wound healing after 14 days, while in the case of control group rats, 48.65% wound contraction was seen after 14 days. Furthermore, the histopathological study revealed that the nSSD gel was more efficient in controlling the wound infection and showed better wound healing as compared with mSSD gel formulation.