Wheat (Triticum aestivum L.) is an important cereal crop in Pakistan which is suffering from major grain production loss because of weed infestations. Control of weeds by herbicides is a primary weed management tool in wheat crop which can be detrimental to the environment and grain produce. Development of an efficient and eco-friendly alternate to the herbicidal weed control, testing the effectiveness of cultural weed control (crop row orientation, selected wheat genotypes and hand weeding) and plants water extracts was undertaken for weed control in wheat. An experiment was run under field conditions in winter season in 2016–2017 and in 2017–2018 in Khyber Pakhtunkhwa Province, Pakistan. The repeated experiment was each time undertaken using a randomized complete block design with a double split plot arrangements at the New Developmental Farm, University of Agriculture, Peshawar, Pakistan. The crop row orientations used were assigned to the main plots. The wheat genotypes used were assigned to the sub-plots. The allelopathic water extracts and hand weeding were assigned to the sub-sub plots. The averaged mean values for row orientations of both the years revealed lowest weed density (95.7 weeds m−2), highest grains per spike (47.3), 1000 grains weight (44.7 g) in north to south row orientation. The averaged mean values of weed density (101.6 weeds m−2), grains per spike (48.2), 1000 grains weight (45.9 g), crude protein content (12.793%), crude fat content (1.533%) and ash content (1.586%) were greater for the wheat genotype Pirsabaq-2013 and Atta-Habib-2010. Water extract of S. halepense, P. hysterophorus, H. annuus and hand weeding showed significantly lower weed density (84.0 to 93.3), grains per spike (50.9 to 48.3), 1000 grains weight (48.3 to 46.2 g), grains protein content (12.280 to 12.209%), grains crude fat content (1.471 to 1.464%) and grains ash content (1.523 to 1.515%). Interaction effect of different tested weed control treatments i.e. N-S × Pirsabaq-2013 and Atta-Habib-2010 × water extract of S. halepense, P. hysterophorus and H. annuus were found to show further reduction in weed density and enhance grains per spike and grains nutrition contributing parameters. Our results show that sowing wheat genotypes Pirsabaq-2013 and Atta-Habib-2010 in north-to-south row orientation, and application of water extract of S. halepense, P. hysterophorus, H. annuus can give an effective weed management and increased quality grain yield of wheat.