Safflower is a multipurpose crop with several uses that can offer benefits to rainfed cereal-based cropping systems due to its tolerance to cold, drought, salinity, and its reduced need for agricultural inputs. Safflower requires good weed control for optimum yields because it is a very poor competitor with weeds, especially at the early growth stage, but registered pre-emergence herbicides are not available. This research investigated the effects of several pre-emergence herbicides on weed control and the yield of safflower in central Italy, through two field experiments in 2019 and 2020. Aclonifen, metazachlor, s-metolachlor, propyzamide, and metribuzin were applied as pre-emergence herbicides. The main weeds were the following: Papaver rhoeas L., Conyza canadensis (L.) Cronq., and Ammi majus L. in experiment 1, and wild sunflower (Helianthus annuus L.) in experiment 2. Metazachlor and metribuzin gave the highest phytotoxicity on safflower in both experiments, with values ranging from 48% to 75% and from 30% to 75% (in a scale of 0–100%), respectively, and seem to be not advisable as pre-emergence herbicides. Aclonifen, s-metolachlor, and propyzamide can be considered selective and safe to the safflower, showing the lowest values of phytotoxicity that ranged from 0 to 10%. Metazachlor and s-metolachlor gave the highest total weed control with values of 92% and 97%, respectively.