Roegneria kamoji Ohwi (Poaceae), a wild relative plant of wheat which is widely distributed across China, has become a dominant and problematic weed in wheat fields in some regions. We have previously confirmed that R. kamoji is highly tolerant to foliar-applied acetyl-CoA carboxylase (ACCase) and acetolactate synthase (ALS) inhibitors in wheat (Triticum aestivum L.). The sensitivity of R. kamoji to pre-emergence (PRE) herbicides and the basis of fenclorim increase selectivity to butachlor between wheat and R. kamoji were evaluated in this study. Screenhouse bioassay showed that R. kamoji exhibited similar sensitivity to wheat to PRE herbicides at their recommended field doses (RFD); it also showed that buatchlor provides the highest relative control for R. kamoji (53.4% emergence and 81.5% fresh weight reduction, respectively), while it had no impact on seedling emergence of wheat among the six PRE herbicides. When butachlor was applied at four-fold RFD, no R. kamoji seedlings emerged; however, it significantly reduced the above-ground biomass of wheat compared with the non-treated control. Pre-treatment with herbicide safener fenclorim by seed soaking increased the ED10 value of butachlor to wheat from 221.8 to 1600.1 g a.i. ha−1, thus increasing the selectivity index from 9.6 to 68.9 between wheat and R. kamoji. The activities of α-amylase activity and protein content during germination, and glutathione-S-transferase (GST) and β-ketoacyl-CoA synthase (KCS) in the seedlings, could be induced by butachlor in both wheat seeds with or without fenclorim pre-soaking. These results suggested that butachlor provides the highest control for R. kamoji and did not affect germination and emergence in wheat. The basis of fenclorim-increased selectivity to butachlor was associated with the induced GST and KCS-mediated enhanced herbicide metabolism in wheat.