An important requirement prior to initiating endodontic or operative dental treatment is the ability to achieve and maintain profound anesthesia. Also Injection of local anaesthetics is one of the most feared or anxiety-inducing stimuli in dental operatory. The fear of pain attributed to injection of anaesthetic agents is cited as an obstacle in providing appropriate dental care. Accomplishing profound pulpal anesthesia without any pain during endodontic treatment is a challenge.Local anaesthesia is defined as a loss of sensation in an area of the body caused by a depression of excitation in nerve endings, or an inhibition of the conduction process in peripheral nerves. Buccal infiltration using 2% lignocaine hydrochloride with epinephrine (LE) is considered to be one of the standard anesthetic techniques for achieving pulpal anesthesia during root canal therapy of maxillary molars. But in patients with irreversible pulpitis there is increased chance of anesthetic failure. The increased failure rate can be attributed to 2 major reasons. The first reason is having local acidosis caused by tissue inflammation. This leads to ion trapping of local anesthetic molecules in ionized form, causing a decrease in the number of local anesthetic molecules crossing the nerve membrane.Secondly, and a more accepted reason, is the activation of nociceptors by inflammatory mediators. A successful treatment outcome can be achieved only by overcoming patients’ fear along with complete and profound anesthesia. This might be possible with cryotherapy which is defned as the application of cold to a localized part of the body in order to block the conduction of nerve impulses . Exertion of cold not only reduces pain from edema and local inflammation but also accelerates and potentiates the nerve blocking effect of the local anesthetics. The efficacy of cold refrigerated lignocaine (4–6 °C) has been found to be effective with a faster onset and longer duration of inferior alveolar nerve block in mandibular molars diagnosed with SIP in an earlier study. In addition, literature evidence also suggests that topical cooling of injection site with ice sticks prior to infiltration anesthesia significantly reduced the pain on injection. The combination of topical ice application and injection of precooled LE effectively decreases the pain on injection. Further, administration of precooled 2% lignocaine HCl with epinephrine at 4–6 °C significantly reduces the time of onset of anesthesia associated with higher success rates, thereby eliminating the need for any supplemental injections when compared to conventional room temperature lignocaine HCl with epinephrine. Photobiomodulation has been considered nowadays as an adjunct to local anesthesia in the management of endodontic pain.Photobiomodulation processes can be studied at the local, regional, and systemic levels. As one of the intracellular processes, increasing mitochondrial metabolic activity leads to increased production of adenosine triphosphate (ATP), nitric oxide (NO), and reactive oxygen species (ROS). A photo-induced ROS stress response has been proposed as an essential component in laser induced analgesia.Hence, the purpose of this study is to compare and evaluate the combined effect of topical cooling of the injection site and administration of cold 2% lignocaine hydrochloride with 1:80,000 epinephrine against photobiomodulation of injection site prior to administration of 2% lignocaine hydrochloride with 1:80,000 epinephrine on onset of action, anesthetic efficacy, and pain on injection during infiltration anesthesia of maxillary molars with symptomatic irreversible pulpitis.