We conducted a long-term nitrogen (N) fertilizer study in an irrigated no-till continuous corn system to assess the effects of N rates on N losses, N use efficiency (NUE), and changes in soil N content. The NUE of the harvested grain (NUEHG), calculated using the difference method (difference between fertilized and non-fertilized [control] experimental units), was 49, 46, 35, and 29% for the annual N fertilizer applications of 67, 132, 196, and 246 kg N ha−1 y−1, respectively during the 2006 to 2018 growing seasons. The system N loss (difference between N inputs and outputs) from N-fertilized treatments, calculated using an N balance from fall 2005 to fall 2018 that included N changes in the 0 to 120 cm soil depths, ranged from 19% with the 67 kg N ha−1 y−1 rate to 57% with the 246 kg N ha−1 y−1 rate. The data suggest that nitrate (NO3–N) leaching and atmospheric emissions could be pathways for these losses. The changes in soil N content were negative, with an average system N loss across fertilized treatments of 15 kg N ha−1 y−1 of soil organic N (SON) in the top 30 cm of soil of the fertilized and non-fertilized treatments. These results show that even no-till systems could potentially have significant net N loss, including a reduction in SON and particulate organic N (POM–N), and that higher N use efficiencies found using the system N balance (NUESys) approach indicate that the NUEHG does not accurately assess the N lost to the environment.