Bulk leaf carbon isotopic composition (δ13Cbulk) has been widely used to investigate leaf level water use efficiency (WUEl) in efforts to boost grain yield relative to crop water use. Although widely used for isotopic analyses, the bulk leaf represents a complex mixture of compounds. Single‐compound isotopic analyses carry diagnostic advantages over bulk analyses in a range of applications and may also serve as surrogates for WUEl and grain yield in crops. This study tests whether compound‐specific carbon and hydrogen isotopes of leaf wax n‐alkanes (δ13Calk and δDalk) and n‐alcohols (δ13Calc) could be used as surrogates for WUEl and grain yield using conventional δ13Cbulk as a reference. Ten winter wheat (Triticum aestivum L.) cultivars were planted under two irrigation treatments (full and deficit irrigation) at Uvalde (wet location) and Amarillo (dry location), TX, during two growing seasons. There were significant relationships between δ13Calk or δDalk and δ13Cbulk, indicating they can all serve as surrogates for WUEl in most cases. Compared with δ13Cbulk, we found stronger relationships between δ13Calk at Uvalde or δDalk under deficit irrigation at Amarillo and grain yield. The δ13Calk also had higher broad‐sense heritability than δ13Cbulk, indicating larger cultivar effects in δ13Calk than in δ13Cbulk. In contrast, the δ13Calc was not consistently related with δ13Cbulk or grain yield. Our study introduces the idea that δ13Calk and δDalk may supplement conventional δ13Cbulk with potential to assist in the breeding process when selecting for high‐WUE and high‐yielding cultivars.