Objective: Preoperative negative affect is a risk factor for worse postoperative pain, but research investigating this association among patients undergoing thoracic surgery is inconsistent. Additionally, female patients often report greater negative affect and postoperative pain than males. This prospective observational study investigated the association between preoperative negative affect and postoperative pain after thoracic surgery and whether this association differed by sex. Methods: Patients (n = 105) undergoing thoracic surgery completed preoperative assessments of pain and negative affect (PROMIS anxiety and depression short forms). Patients reported their daily worst pain over the first 7 postoperative days, and an index score of acute postoperative pain was created. Six months after surgery, a subsample of patients (n = 60) reported their worst pain. Results: Higher levels of preoperative anxiety (r = 0.25, p = 0.011) and depression (r = 0.20, p = 0.042) were associated with greater acute postoperative pain, but preoperative negative affect was not related to chronic postsurgical pain (anxiety: r = 0.19, p = 0.16; depression: r = −0.01, p = 0.94). Moderation analyses revealed that the associations between both preoperative anxiety (b = 0.12, 95% CI [0.04, 0.21], p = 0.004) and depression (b = 0.15, 95% CI [0.04, 0.26], p = 0.008) with acute postoperative pain were stronger among females than males. Similarly, the association between preoperative anxiety and chronic postsurgical pain was stronger among females (b = 0.11, 95% CI [0.02, 0.20], p = 0.022), but the association between preoperative depression and chronic pain did not differ based on sex (b = 0.13, 95% CI [−0.07, 0.34], p = 0.201]). Conclusions: Our findings suggest that negative affect may be especially important to the experience of pain following thoracic surgery among female patients, whose degree of preoperative anxiety may indicate vulnerability to progress to a chronic pain state. Preoperative interventions aimed at reducing negative affect and pain may be particularly useful among females with high negative affect before thoracic surgery.