Resistance breeding is an effective and sustainable disease management strategy, but sometimes can be associated with yield costs and other trade-offs. I measured the effects (direction and magnitude) of northern leaf blight (NLB) resistance in maize at the locus level using near-isogenic lines (NILs), and at the population level using a population of diverse hybrids. I also conducted a genome-wide association study (GWAS) for NLB resistance and other traits on the diverse hybrid population and used drone-based high-throughput phenotyping for resistance and yield. I found that locus-driven NLB resistance may have yield penalties in the homozygous state and that is traded-off with northern leaf spot (NLS) susceptibility. I also identified two multiple disease resistant (MDR) NILs for NLB, anthracnose top dieback (A TD), and anthracnose stalk rot (ASR). At the population level, NLB resistance was not associated with yield penalties in the absence of disease. Significant GWAS hits were found for root lodging, stalk lodging, and grain moisture under NLB pressure, but not for NLB. The drone-derived vegetation indices that I extracted from field plots can be used potentially as surrogates or indirect selection criteria for resistance and yield. However, this high-throughput phenotyping technology needs improvement under realistic and typical field conditions of breeding trials. This research has implications for the optimization of maize breeding programs.