Aim The study recorded 400 responses from 301 patients, aged 6-93, who all had carious lesions prepared with the erbium, chromium: yttrium-scandium-gallium-garnet (Er,Cr:YSGG) 2780-nm laser system. Different parameters, including gender, delivery method, power settings, tooth position, class type of cavity preparation, and patients' age, were compared and analyzed for possible predictive values in anticipating the patients' pain experience. Methods Class 1-5 cavity preparations were made using the Er,Cr:YSGG laser. All carious lesions fit ICDAS code 4-5 classifications. Power setting of 3.75 W was used for posterior teeth class 1-4 preparations and 2.5 W for all primary teeth, permanent anterior teeth, and all class 5 preparations. Nonanxious patients, who agreed to start cavity preparation without a local anesthetic, were instructed to stop the procedure and ask for an anesthetic injection, should they perceive a level of pain greater than their tolerance level. Anxious patients were not included in this study. Pain perception using the visual analog scale (VAS) along with the percentage of patients who needed a local anesthesia injection were recorded. The data was then analyzed using one-way ANOVA test, at significance level of α = 0.05, and Tukey pair-wise comparison, at 95% confidence interval. Results Eighty-five percent of cavity preparations were pain free; 15% of the preparations were found to have a degree of pain associated with them. However, only 6% requested a local anesthetic injection. There was no significant difference found between the two methods of delivery: gold handpiece (HP) vs. turbo HP. No significant differences were observed between males and females, regarding pain perception (13% vs. 18%, respectively). Posterior teeth were significantly more sensitive to laser cavity preparation, compared to anterior teeth, as indicated by the VAS pain scores (P value = 0.0001). Regarding anterior teeth, class 5 was significantly more sensitive to laser cavity preparations, when compared to class 1. In posterior teeth, there were no statistically significant differences between class 1 and 5, although pain perception was the most prevalent in class 2 preparations. Using higher-power settings (3.75 W vs. 2.5 W) for cavity preparation, the resulting pain response was significantly higher, as indicated by the VAS pain scores (P value = 0.0001). As the patients' age increases, the frequency of those experiencing pain decreases, with the exception of a sudden spike for the cohort aged 26-35, who proved to be the most sensitive to laser cavity preparation; this group was significantly different from all other age groups (P value = 0.0001). Conclusions The Er,Cr:YSGG laser system is an effective method for pain-free cavity preparations for 85% of the general patient population, who do not suffer from dental anxiety. Certain patient selection criteria, including age, power settings, and class type of cavity preparation, are important in achieving an overall positive and pain-free expedience.