Abstract <p>Weeds are commonly regarded as the primary cause of nutrient depletion in wheat fields, resulting in decreased crop yield. In order to address this issue, a two-year field study was conducted to determine the most effective combination of herbicides and fertilizers for weed control in wheat, while considering certain physiological factors. Five levels of herbicides (weed infested no-herbicide, weed free no-herbicide, 2,4-D, Tribenuron-methyl, and Othello) and four levels of fertilizers (no fertilizer, amino acid, seaweed, NPK) were arranged in a factorial design based on RCBD with three replications. Results exhibited that weed infestation decreased the relative water content (RWC), membrane stability index (MSI), chlorophyll <i>a</i>, <i>b</i>, carotenoids, and grain yield of wheat, whereas proline and malondialdehyde (MDA) content, and the activities of catalase (CAT), peroxidase (POX), and ascorbate peroxidase (APX) enzymes increased. In plots treated by 2,4-D, the control treatment (without fertilizing) showed the maximum reductions in weed density and biomass, however, it had the least negative effect on the most of the wheat physiological parameters. By utilizing the 2,4-D herbicide to manage weeds, the NPK treatment demonstrated the most significant combined impact in decreasing the density and biomass of weeds. Additionally, it improved RWC, MSI, as well as the content of chlorophyll <i>a</i>, <i>b</i>, and carotenoids in wheat. To summarize, wheat growers should be mindful of the combined and collaborative impacts of herbicides and fertilizers. This cooperative effect can be harnessed to diminish the detrimental effects of weeds, thereby increasing the potential and quality of crop yield.</p>