Potassium is an essential macronutrient, where its availability regulates numerous biochemical, phenological, and physiological responses in plants. Synchronizing potassium supply with plant demand is a key factor to enhance growth and grain production of wheat grown in cadmium-contaminated saline soils. Field experiments were conducted in El Fayoum province, Egypt, between latitudes 29° 02′ and 29° 35′ N and longitudes 30° 23′ and 31° 05′ E, during the cropping seasons of 2017–2018 and 2018–2019 to determine the influence of different applied potassium rates and times on nutrient uptake and wheat yield grown under Cd-contaminated saline soil (ECe = 8.53 dS m−1 and Cd = 18 mg kg−1 soil). Four K levels (K0, K40, K80, and K120 representing 0, 40, 80, and 120 kg ha−1) were applied at different application times [full dose (basal) at sowing (100% S), two equal split doses at sowing and flowering stage (50% S + 50% F), and full dose at flowering stage (100% F)]. The experimental treatments were arranged in a randomized split complete block design and replicated three times. The applied K rates, times, and their interaction induced significant differences in nutrient uptake and physiological responses which in turn improved the growth and yield of the wheat crop. Potassium addition with 120 kg ha−1 at two equal split doses (50% S + 50% F) resulted in the highest values of plant height (97 cm), Fv/Fm (0.83), PI (5.49), SPAD (58.63), MSI (34.57), seed yield (5.04 t ha−1), straw yield (9.04 t ha−1), and water productivity (0.99 kg m−3). Similarly, the uptake of N, P, K, Ca, Mg, Fe, Mn, and Zn was increased, while the uptake of Na and Cd decreased as the K supply increased under the split application. The addition of potassium by 120 kg ha−1 in two equal split doses at the sowing and flowering stage could be a valuable approach to improve yield and yield quality of wheat crop grown under cadmium-contaminated saline soils.