While On-Farm Experimentation (OFE) has great value to farmers, it inevitably comes secondary to their core businesses; this can lead to risks of experimental errors, abandonment at busy times, or limited time for planning. Hence, OFE must use practical approaches to minimize disruption to farming practices and additional workloads on farmers while maintaining experimental quality. Based on extensive experience conducting research with farmers, we propose five principles for OFE success: 1) collaboration, 2) simple treatments, 3) consideration of underlying variations, 4) replication, and 5) assessments planned in advance. Principles 2–4 are supported by a meta-analysis of over 300 experiments that analyzed factors that can affect the precision of yield-map analyses. All five principles are illustrated by the successes and failures of experiments run in 2022 by a ‘Crop Nutrition Club’ of seventeen farmers and Association of Independent Crop Consultants (AICC) agronomists to explore optimal fertilizer rates and products for cereal crops.