Reward-seeking behavior is essential for survival and is greatly influenced by experience, internal states, and physiological factors such as sleep. The nucleus accumbens (NAc) is reward processing hub that integrates external and internal signals to regulate reward-seeking behaviors. However, it is not well understood how NAc activities during reward seeking may be shaped by learning experience, and to what extent that it may be subject to physiological regulations such as sleep. Here, we used in vivo fiber photometry to monitor calcium (Ca) activities in the NAc of male and female mice undergoing sucrose self-administration (SA) training. We found that the NAc Ca dynamics during sucrose SA were related to the behavioral outcome and evolved over different training stages. Moreover, acute sleep deprivation increased sucrose SA while reduced NAc Ca responses and dampened its sensitivity to reward update. Thus, our findings suggest that the NAc response during natural reward seeking is dynamic, adaptive to learning experience, and can be blunted by acute sleep deprivation.