Safflower (Carthamus tinctorius L.) is a multipurpose crop and can be grown successfully under moisture-deficit environments. This study assessed the physiological attributes and yield-related traits of two safflower varieties (Din & ccedil;er and Balc & imath;) under rainfed and irrigated environments during 2019-2020 and 2020-2021. Data relating to physiological and yield-related traits, and soil enzymes were collected. Soil attributes, nutrient acquisition, and yield-related traits were significantly altered by the interactive effect of varieties and growing environments. Higher nitrate (NO3-) accumulation (279.92 and 300 mg N g DW) was recorded in Balc & imath; variety than Din & ccedil;er under rainfed conditions. Higher grain yield was recorded under irrigated conditions compared to rainfed environments. Balc & imath; variety produced 2724 and 2464 kg/ha grain yield, whereas Din & ccedil;er resulted in 2664 and 2565 kg/ha under irrigated conditions during 1(st) and 2(nd) year, respectively. Nevertheless, Balc & imath; produced a higher yield than Din & ccedil;er under rainfed conditions. The results indicate that irrigation is crucial for safflower in arid and semi-arid regions. Similarly, Din & ccedil;er variety is advantageous under rainfed conditions, whereas the Balc & imath; variety may be more beneficial in irrigated areas.