BACKGROUND: This study aimed to assess the effects of hydromorphone as an adjuvant to ropivacaine serratus anterior plane block (SAPB) on postoperative analgesia and inflammatory responses in patients undergoing video-assisted thoracoscopic surgery (VATS). METHODS: This was a prospective, randomized, double-blind clinical trial. A total of 120 lung cancer patients, aged 20-75 years, with an American Society of Anesthesiologists classification of I or II and a body mass index of 18-28 kg/m², were randomly assigned to three groups: ropivacaine combined with hydromorphone SAPB (HR group), ropivacaine SAPB (R group), and control (C group). Ultrasound-guided deep SAPB was used to inject medications. The main observed indicators were postoperative visual analog scale (VAS) pain scores, serum inflammatory markers (C-reactive protein (CRP), IL-6, TNF-α), intraoperative medication dosage, postoperative complication rates, and analgesic effects. RESULTS: Postoperative VAS pain scores were significantly reduced in the HR and R groups compared to the C group, especially at 6 h postoperatively. The median VAS score in the HR group was 2.00 (inter-quartile ratio (IQR): 2.00, 2.00), which was significantly lower than that of the C group's score of 3.00 (IQR: 3.00, 3.00; P < 0.001). The CRP levels at 24 and 48 h postoperatively in the HR group were 23.80 mg/L and 21.65 mg/L, respectively, significantly lower than the C group's levels of 56.65 mg/L and 82.75 mg/L, P < 0.001. The levels of IL-6 and TNF-α were also significantly lower in the HR group than in the C group. Intraoperative propofol and remifentanil dosages in the HR group were reduced to 5.22 mg/kg/h and 7.59 µg/kg/h, respectively, lower than the C group's dosages of 5.93 mg/kg/h and 5.74 µg/kg/h, P < 0.001. The incidence of postoperative nausea and vomiting in the HR group was 12.5%, which was lower than that in Group C (35.7%, P = 0.032). CONCLUSION: Ropivacaine adjuvant with hydromorphone in SAPB reducing postoperative pain and inflammatory in patients undergoing VATS, which contributed to rapid recovery. However, future studies should explore the long-term benefits and concenntration of hydromorphone of SAPB before it taken into clinical use. TRIAL REGISTRATION: Chinese Clinical Trial Register on August 19, 2021, NCT number ChiCTR2100053893.