The impact of proline, methionine, and melatonin on cauliflower plants under drought stress is still unclear in the available publications. So, this research aims to study these biochemical compounds’ effects on cauliflower plants grown under well-irrigated and drought-stressed conditions. The obtained results showed that under drought-stressed conditions, foliar application of proline, methionine, and melatonin significantly (p ≤ 0.05) enhanced leaf area, leaf chlorophyll content, leaf relative water content (RWC), vitamin C, proline, total soluble sugar, reducing sugar, and non-reducing sugar compared to the untreated plants. These treatments also significantly increased curd height, curd diameter, curd freshness, and dry matter compared to untreated plants. Conversely, the phenolic-related enzymes including polyphenol oxidase (PPO), peroxidase (POD), and phenylalanine ammonia-lyase (PAL) were significantly reduced compared to the untreated plants. A similar trend was observed in glucosinolates, abscisic acid (ABA), malondialdehyde (MDA), and total phenols. Eventually, it can be concluded that the foliar application of proline, methionine, and melatonin can be considered a proper strategy for enhancing the growth performance and productivity of cauliflower grown under drought-stressed conditions.