Manganese (Mn) deficiency in human nutrition is widespread in the rice–wheat cropping system where cereal grains are the staple food. Agronomic biofortification is an innovative and pragmatic approach to tackle Mn malnutrition. A 2-year field study was conducted to investigate the comparative effect of different Mn application methods: (1) No Mn application, (2) Mn seed coating (2 g kg−1 seed), (3) hydro-priming, (4) Mn seed priming (0.1 M Mn solution), (5) soil application (0.5 kg ha−1), (6) foliar water spray, and (7) foliar Mn spray (0.02 M Mn solution) in improving the productivity, profitability, biofortification and Mn-use efficiencies of rice in puddled transplanted flooded rice (FR) and direct-seeded aerobic rice (AR) production systems. Under AR system, soil physical and biological properties, as well as nutrient dynamics were improved. Averaged across 2 years, improvement in total soil porosity (9%), soil organic carbon (12%), soil microbial biomass carbon (6%), soil microbial biomass nitrogen (3%), total nitrogen (13.6%), available phosphorus (10.98%), and exchangeable potassium (7.1%) were noted in AR system over FR system. Regardless of application methods, Mn nutrition substantially improved the yield and related traits and grain Mn concentration in both production systems. Averaged across 2 years, the increase in grain yield under different Mn application treatments was in the order: foliar application (22%) > seed priming (16%) > soil application (12%) > seed coating (12%). Grain Mn concentration was the highest with foliar application of Mn (27% over control) in both production systems. Moreover, the maximum net benefits and benefit–cost ratio were obtained through Mn-foliar application in both production systems. In conclusion, Mn application by either method improved the productivity, profitability, biofortification and Mn-use efficiencies under FR and AR systems; nevertheless, foliar Mn application performed better for all the studied traits.