Water stress is the most important environmental factor limiting crop yield in the southern High Plains. Drought tolerant crops along with deficit irrigation strategies may be promising for sustainable agriculture in the region. The objective of this study was to assess water relations, photosynthesis, yield-forming components, and yield of spring safflower (Carthamus tinctorius L.) cultivars under growth stage based irrigation management. A blocked split plot design was used with irrigation treatments (fully irrigated [FI], stress at vegetative stage [VS], stress at reproductive stage [RS], and dryland [DL]) as the main plot and cultivars (PI8311, 99OL and Nutrisaff) as subplot in four replications. Measurements of water potential (ᴪl) indicated that irrigation treatments imposed water stress on safflower. Safflower responded to stress by regulating stomata and osmotic adjustment. Water stress significantly reduced photosynthesis (Pn), leaf area index (LAI) and light interception in all stress treatments, resulting in decreased biomass accumulation. Seed yield of safflower was strongly related to biomass production (R2 = 0.61). Among yield-forming traits, heads per plant were more influential in yield formation than seeds per head and 1000-seed weight. Compared to the FI treatment, RS treatment reduced seed yield by 19 and 20% in 2013 and 2014, respectively; while the same reduction in VS treatment was 25 and 22%, respectively. However, seed yield differences between RS and VS treatments were not statistically significant.