Although nonsteroidal anti-inflammatory drugs (NSAIDs) are often used in anurans, limited pharmacodynamic data are available regarding their value, particularly with regards to repeated dosing. This study investigated the efficacy and safety of serial, once-daily NSAID dosing in smoky jungle frogs (Leptodactylus pentadactylus). Twenty frogs were randomly assigned to receive one of five treatments, once daily for six consecutive days: topical diclofenac (1 mg/kg) or subcutaneous firocoxib (5 mg/kg), ketoprofen (1 mg/kg), meloxicam (0.2 mg/kg), or an equal volume 0.9% saline (control). An acetic acid test was used to determine the nociceptive threshold for each frog 2, 8, 24, 48, and 144 h after initial drug administration. All frogs were euthanized on day 7 for gross examination and histopathology. No significant difference in response was noted for any drug at any time point compared with saline. Mean or median test response for NSAID groups was greater than or equal to saline in 3/4, 2/4, 4/4, 4/4, and 3/4 frogs at 2, 8, 24, 48, and 144 h, respectively. Significant necropsy findings included epidermal necrosis of the hindlimbs in 7/20 frogs (NSAID groups), gastric ulceration in 6/ 20 frogs (NSAID and saline groups), and renal tubular degeneration in 1/20 frogs (NSAID group). None of the aforementioned pathologies were suspected to be secondary to NSAID administration. Further research regarding NSAID pharmacokinetics and pharmacodynamics in anurans is warranted. Topical acetic acid is correlated with epidermal necrosis in smoky jungle frogs.