Wheat (Triticum aestivum L.) – cotton (Gossypium hirsutum L.) system is a major production system in Pakistan, however, cotton yield and quality is declining in the system most likely due to weeds infestation, nutrient stress, population densities (either too low or too high) and intensive tillage practices. Conservation tillage system has been introduced to avoid late sowing of wheat and to reduce the land preparation cost in wheat-cotton system. Conservation tillage such as reduced and zero tillage in combination with appropriate herbicide, optimum N and intra-row spacing may have the potential to enhance cotton yield and quality on sustainable basis. The objective of this study was to determine the effect of post-emergence herbicides, nitrogen rates and intra-row spacing under different tillage systems on cotton yield and quality in wheat-cotton system. Three field experiments were conducted at Cotton Research Station, Ratta Kulachi, Dera Ismail Khan, Pakistan, during 2010 and 2011. In experiment 1, post-emergence herbicides, i.e. haloxyfop-R-methyl 10.8 EC (108 g a.i. ha-1), lactofen 24 EC (168 g a.i. ha-1), haloxyfop 10.8 EC + lactofen 24 EC, hand weeding, weedy check and three tillage systems [zero tillage (ZT), reduced tillage (RT) and conventional tillage (CT)] were studied. In experiment II, five nitrogen levels (0, 50, 100, 150, and 200 kg N ha-1) and three tillage systems (as in experiment I) while in experiment III, four intra-row spacing (15, 22.5, 30, 37.5cm) and three tillage systems (as in experiment I) were evaluated in randomized compete block design (RCBD), with split plot arrangements, replicated 4 times. Tillage was allotted to main plots in all the experiments while herbicides, N rates and intra-row spacing were applied to subplots in experiment I, II and III, respectively. Mean of the two years data revealed that broad spectrum herbicides (Haloxyfop + Lactofen) and hand weeding reduced weed density by 78 and 93 %, respectively, compared to all other weed control treatments. Interaction effects revealed that RT in combination with broad spectrum herbicides had maximum weeds reduction percentage (95%). RT with broadspectrum herbicides had higher plant height, more bolls plant-1, boll weight, ginning out turn, seed cotton yield, fiber length, fiber strength and fiber fineness compared to ZT and CT. It is concluded that broad-spectrum herbicides under RT produced higher cotton yield and fiber quality in wheat based cropping system on silty clay soil of D.I.Khan. In experiment II, nitrogen (N) and tillage interaction is of great economic importance to improve crop yield and N use efficiency. Nitrogen rates had significant differences for yield components and seed cotton yield. Nitrogen rate of 150–200 kg N ha-1 produced highest seed cotton yield due to more bolls plant-1 and greater boll weight. The lower N rate (50-100 kg ha-1) produced the optimum nitrogen agronomic efficiency (NAE, 3.5-4.0 kg kg-1), nitrogen physiological efficiency (NPE, 11-12 kg kg-1), and nitrogen recovery efficiency (NRE, 32-33 %) than higher N rate (150-200 kg ha-1). Tillage × nitrogen interactions revealed that RT had greater bolls plant-1, boll weight, GOT, fiber length, and strength at 150–200 kg N ha-1 compared to other tillage system. The micronaire revealed no difference among tillage systems in fiber fineness. Using 150–200 kg N ha–1 in conservation tillage may be a sustainable approach to enhance cotton yield (3549 kg ha-1) and quality. In experiment III, intra-row spacings significantly affected yield, yield components and quality in both years. The highest seed cotton yield was obtained from 22.5 cm intra-row spacing. Interaction effects revealed that RT × 22.5 cm intra-row spacing produced optimum seed cotton yield. The ginning out turn and fiber strength was higher in RT × 22.5 cm intra-row, except fiber length. In conclusion, RT at 22.5 cm plant to plant spacing produced maximum seed cotton yield (4060 kg ha-1). The overall results suggest that using broad-spectrum herbicides along with reduced tillage, 150–200 kg N ha–1 at a row swpacing of 22.5 cm constitutes a near-optimal system of cotton management in the wheat-cotton system of Dera Ismail Khan.