A solar-powered humidification-dehumidification (HDH) desalination system offers flexible water and power cogeneration, promising in addressing energy crisis. However, the system’s operation frequently deviates from the on-design condition, making it crucial to study its off-design behaviors. This paper develops an off-design model to investigate the operation performance in response to variations in liquid–gas mass flow rate ratio (MFRR) and solar intensity. Furthermore, the heat and mass transfer mechanisms in humidifier and dehumidifier are inquired under specific conditions. The results exhibit that the system performance sensitivity to changes in the liquid–gas mass flow rate ratio and solar intensity aligns with the expectations under on-design conditions. The combined heat and mass transfer process weakens first and then strengthens from the bottom to the top in the humidifier, and vice versa in the dehumidifier. Notably, a higher freshwater flow rate enhances dehumidification efficiency, raising gained-output-ratio (GOR) by 7.13% and water production by 1.5%. Validation experiments confirm the off-design model’s accuracy and credibility, to offer methodological insights for the effective prediction of off-design behaviors.