Objective To evaluate the effect of intravenous infusion of lidocaine combined with magnesium sulfate on perioperative immunological stress in patients undergoing laparoscopic surgery with general anesthesia. Methods Seventy‑six patients, aged 18‒65 y, of the American Society of Anesthesiologists physical status Ⅰ or Ⅱ, undergoing laparoscopic surgery with general anesthesia, were divided into 2 groups (n=38) according to the random number table mothod: experiment group (group L) and control group (group C). The group C received intravenous anesthesia only, while the group L received intravenous anesthesia combined with intravenous infusion of lidocaine combined with magnesium sulfate. Their general information were recorded (including age, height, weight, surgery time and anesthesia time); the percentages of CD3+ T cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells, B cells, and CD4+/CD8+ at the time points of entry (T1), after extubation (T2), and 2 d after surgery (T3) for two groups of patients. Enzyme‑linked immunosorbent assay (ELISA) was used to detect the concentrations of plasma high‑sensitivity C‑reactive protein (hs‑CRP), interferon‑γ(IFN‑γ), prostaglandin F2 (PGF2a), and prostaglandin E2 (PGE2) in two groups of patients. The 15‑item Quality of Recovery (OoR‑15) score and postoperative hospital stay time were recorded. Results There was no statistical difference in general information between two groups (all P>0.05). The QoR‑15 score at T3 in group L is higher than that in group C (P<0.05), while there is no significant difference in postoperative hospital stay time between the two groups (P>0.05). Compared with the percentage at T1: the percentage of CD3+ T cells, CD4+ T cells, and CD4+/CD8+ in group C decreased at T2 (all P<0.05), while the percentage of NK cells increased (P<0.05) at T2; the percentage of NK cells in group L increased (P<0.05) at T2 but decreased at T3 (P<0.05), the percentage of CD4+ T cells and B cells increased (all P<0.05) at T3. Compared with the percentages at T2: the percentages of CD3+ T cells, CD4+ T cells, and B cells increased in both groups at T3 (all P<0.05), the percentage of NK cells decreased (P<0.05); the percentage of CD4+/CD8+ increased in group C at T3 (P<0.05). Compared with group C, group L had a higher percentage of CD4+ T cells but a lower percentage of NK cells at T2 and T3 (all P<0.05). Group L had a higher percentage of CD3+ T cells at T2 than the percentage in group C (all P<0.05). Compared with T1: the concentrations of hs‑CRP and IFN‑γ increased in both groups at T3 (all P<0.05), while the concentrations of PGF2 α and PGE2 decreased in group L at T2 (all P<0.05). Compared with T2: the concentrations of hs‑CRP and IFN‑γ increased in both groups at T3 (all P<0.05), and the concentrations of PGF2α and PGE2 increased in group L at T3 (all P<0.05). Compared with group C: the concentrations of PGF2α and PGE2 decreased in group L at T2 (all P<0.05), and the concentrations of hs‑CRP and IFN‑γ decreased in group L at T3 (P<0.05). There was no significant difference in other indexes between the two groups (all P>0.05). Conclusions Intravenous infusion of lidocaine combined with magnesium can reduce perioperative immunological stress and benefit postoperative recovery in patients undergoing laparoscopic surgery with general anesthesia.