Minimally invasive transforaminal lumbar interbody fusion (TLIF) offers equivalent postoperative fusion rates compared to posterior lumbar fusion (PLF) and minimizes the amount of iatrogenic injury to the spinal muscles. The objective of this study was to examine the difference in pain perception, stress, mood disturbance, quality of life, and immunological indices throughout the perioperative course among patients undergoing TLIF and PLF. A prospective, nonrandomized descriptive design was used to evaluate these measures among patients undergoing TLIF (n = 17) or PLF (n = 18) at 1 week prior to surgery (T1), the day of surgery (T2), 24 hours postoperatively (T3), and 6 weeks postoperatively (T4). Among TLIF patients, pain, stress, fatigue, and mood disturbance were significantly decreased at the 6-week followup visit (T4) compared to patients who underwent PLF. The TLIF group also demonstrated significantly higher levels (near baseline) of CD8 cells at T4 than the PLF group. Interleukin-6 levels were significantly higher in the TLIF group as well, which may be an indicator of ongoing nerve regeneration and healing. Knowledge concerning the effect of pain and the psychological experience on immunity among individuals undergoing spinal fusion can help nurses tailor interventions to improve outcomes, regardless of the approach used.