Inter-specific hybridizations especially using wild species can be used for increasing genetic diversity and developing new varieties. This research was done to assess genetic diversity, drought tolerance and inheritance of different traits in seven F2 populations obtained from direct and reciprocal crosses of three safflower species including C. tinctorious , C. palestinus and C. oxyacanthus. Two genotypes of cultivated safflower brifly “I” and “C” were crossed with C. palestinus (P) and C. oxyacanthus (O) in both directions. The plant materials were evaluated at two moisture environments (normal and drought stress) according to a completely randomized block design. The results indicated that drought stress had significantly decreased most measured characteristics including day to flowering, day to maturity, plant height, number of branches per plant, capitula diameter, number of capitula per plant, 100-grain weight, number of grain per capitula, grain yield per capitula and grain yield per plant. The crosses obtained from C. palaestinus with cultivated species had better performance at both moisture conditions when compared to other crosses in respect to grain yield and its components. The highest broad sense heritability at the two moisture conditions belonged to capitula length and the lowest was related to the number of capitula per plant. The results of principle component analysis (PCA) showed that the first three-components justified 82.96 and 84.98% of all variance in the non-stress and drought stress conditions, respectively. According to the Means Productivity (MP), Stress Tolerance Index (STI), Geometric Mean Productivity (GMP) and Stress Non-stress Production Index (I)indices, the crosses of PI, IP, CP and PC had the highest tolerance to drought being approved by the results of bi-plot of PCA. Among the used indices, STI, GMP and I were identified as the best ones for selecting the most tolerable crosses to drought stress. Stepwise regression analysis indicated that grain yield per capitula and number of capitula per plant were more important for determining grain yield which can be used for indirect selection to improve grain yield in breeding projects. Results of inheritance study showed that the leaf edge at rosette stage, spin, spin of the bracket tip, shape of Bracket, orientation of bracket tip and shape of seed, had complete dominance gene action (segregation ratio of 3:1). In evaluating characteristics like the shape of rosette leaf and bracket size, incomplete gene action was observed (segregation ratio of 1:2:1). In assessing the flower color of PI and IP crosses, the incomplete dominance gene action was also seen (segregation ratio of 1:2:1) and for other crosses, various epistatic genetic effects was observed. The results of grain color inheritance in PO, CO and IO crosses showed the dominant epistasis (segregation ratio of 12:3:1). Keywords : Safflower, Inter-Specific Hybridizations, Drought Stress, Gene Action