Aiming at the problem that the online detection of moisture regain of seed cotton during cotton picking operations is significantly interfered by environmental temperature and contact pressure, a moisture regain sensor for seed cotton in cotton pickers was designed based on the resistive method, integrating temperature and pressure compensation mechanisms. By optimizing the resistance detection circuit to broaden the measurement range and combining temperature and pressure sensing units, a sensor hardware system capable of synchronously collecting environmental temperature, contact pressure, and seed cotton resistance was designed, and it was calibrated and performance tested. An experimental platform was built to analyze the influence of temperature, pressure, and moisture regain on the conductive characteristics of seed cotton, and a moisture regain prediction model incorporating multi-parameter compensation was established. The results showed that the designed hardware circuit had an average absolute error of less than 0.4℃ for temperature measurement, an average relative error of less than 0.2% for pressure measurement, and an average relative error of less than 3% for resistance measurement. In the moisture regain prediction model, the BPNN algorithm performed best, with a coefficient of determination (R2) of 0.986 and a root mean square error (RMSE) of 0.377%. To verify the reliability of the moisture regain sensor, indoor static tests and field harvesting tests were conducted. The indoor static test results indicated that the sensor’s detection range was from 4% to 15%, with an average absolute error of 0.22% and an average relative error of 2.32%. The field harvesting test results showed that the absolute error of the detection results was no greater than 0.5%, and the relative error was no greater than 4.32%. The tests demonstrated good accuracy and practicality, providing effective technical support for the online detection of moisture regain of seed cotton in cotton pickers.