Field experiment was conducted in naturally Striga hermonthica (Witchweed) infested field in the Kassena-Nankana East district of the upper East region, Ghana during the 2018 cropping season. This was to investigate effects of Striga tolerant pearl millet varieties intercropped with cowpea on S. hermonthica and crop yield. The study was done in a 4 x 3 factorial experiment consisting of four pearl millet varieties (Akad-kom, Kaanati, Naad-kohblug and Waapp-naara) and three cropping patterns (sole millet, millet-cowpea (1:1) and millet-cowpea (2:1) laid out in a randomized complete block design with three replications. Results showed that Striga emergence and shoot biomass was highest with Waapp-naara variety, which led to low grain yields (1.78 t/ha). Grain yield of Akad-kom (1.89 t/ha) was outstanding with millet-cowpea (1:1) as the best cropping pattern. Millet-cowpea (1:1) cropping pattern had the lowest Striga numbers and shoot biomass. Naad-kohblug variety and MC (1:1) cropping pattern gave best total LER of 1.44 and 1.41, respectively. Grain yield negatively correlated with Striga count (r = -0.42). Millet-cowpea (1:1) cropping pattern exhibited suicidal germination of Striga seeds, enhanced soil fertility and promoted Striga seed bank depletion of 46%. Resource poor farmers in Striga endemic areas could plant Akad-kom and Naad-kohblug varieties as sole crops or intercropped with cowpea (1:1) to manage Striga hermonthica and maximize grain yields.