The effects of the irrigation regime and different fertilizer sources on the eco-physiological responses and yield characteristics of dragon’s head were explored in a factorial experiment based on a randomized complete block design with 12 treatments and 3 replications in the 2019 growing season. The treatments included six different fertilizer sources (animal manure, vermicompost, poultry manure, biofertilizer, chemical fertilizer, and control) and two irrigation regimes (rainfed and supplemental irrigation). The results indicated the positive effects of supplementary irrigation and the application of vermicompost, poultry manure, and animal manure by increasing the absorption of nutrients (phosphorus and potassium) and improving relative water contents, chlorophyll and carotenoid contents, and the fixed oil percentage of dragon’s head. The activities of catalase, ascorbate peroxidase, and superoxide dismutase decreased in the rainfed plants, whereas organic fertilizer application increased the antioxidant enzyme activity. The highest grain yield (721 kg ha−1), biological yield (5858 kg ha−1), total flavonoids (1.47 mg g−1 DW), total phenol (27.90 mg g−1 DW), fixed oil yield (200.17 kg ha−1), and essential oil yield (1.18 kg ha−1) were noted in plants that were treated with vermicompost under supplemental irrigation. Therefore, it is recommended that organic fertilizers such as vermicompost and poultry manure be used to substitute chemical fertilizers. These practices can help popularize organic crops using rainfed and supplementary irrigation.