A green, novel, rapid, and efficient protocol is developed for the synthesis of various Schiff bases from 4-amino-2-thioxo-1,3-diazaspiro[5.5]undec-4-ene-5-carbonitrile using ammonium chloride as a very inexpensive and readily available reagent in refluxing ethanol. High yields, easy work-up, and short reaction times are advantages of this environmentally benign procedure. The prepared compounds were screened for their anti-inflammatory activity “at a dose of 10 mg/kg body weight,” which revealed promising activities relative to indomethacin used as a reference standard in this study.