Root canal treatment (RCT) eliminates damaged pulpal tissue and protects the tooth from recurrent microbial invasion. Post-endodontic pain (PEP) is a frequently encountered complication of root canal therapy. It can have an impact on patients’ quality of life (QoL) and their subjective perception of treatment options. Thus, a self-assessment questionnaire was used to evaluate and compare the influence of manual, rotary, and reciprocating file shaping procedures on immediate post-operative quality of life (POQoL) involving single-visit root canal therapy. It was a double-blinded, randomized, controlled clinical trial. A total of 120 participants were randomly assigned sequentially to three groups comprising 40 patients in each group: Group A: Hand K file (positive control); Group B: ProTaper Next file system; and Group C: WaveOne Gold. Post-operative pain was evaluated using a 4-point visual analog scale (VAS) after 12 h, 24 h, 48 h, 72 h, and 1 week. The highest post-operative pain was with manual instrumentation using hand K files, and the lowest was with reciprocating and rotating instrumentations. No significant difference was noted between the parameters of quality of life assessed, suggesting the filing system or technique had a similar effect.