The aim of this study was to evaluate the association of perineural invasion (PNI) with a depth of invasion (DOI) and neck node metastasis in patients with squamous cell carcinoma (SCC) of the oral cavity. A total of 201 eligible patients with histopathologically confirmed SCC of the oral cavity were enrolled. Patients were analyzed in two arms, Arm A (PNI-positive) and Arm B (PNI-negative). The clinicopathological profile along with the association of DOI and neck node metastases with PNI were studied in both arms. All data were analyzed using SPSS version 22. Among 201 patients, the majority were from carcinoma of the buccal mucosa (91,45.3%), followed by the oral tongue (59,29.4%). Histopathological evidence of PNI was present in 107 (53.2%), DOI of more than 4 mm was seen in 165 (82.1%), and less than or equal to 4 mm was seen in 36 (17.9%) patients. Out of 102 PNI-positive patients, 64 (62.7%) had positive neck node metastasis, whereas out of 89 PNI-negative patients, 39 (43.8%) had positive neck node metastasis. This association of PNI with neck node metastases was found to be significant (p = 0.013). Here, 10 patients had unknown nodal status. The association of PNI with DOI was found to be statistically significant (p = 0.00). Out of 165 patients with DOI greater than 4 mm, 101 (61.2%) were PNI positive, while out of 36 patients with DOI less than equal to 4 mm, only 6 (16.6%) were PNI positive. PNI was also found to be associated with lymphovascular space invasion (p = 0.00) or extracapsular extension (p = 0.001) and was statistically significant. The presence of PNI in oral cavity cancers is found to be strongly associated with DOI and neck node metastases, suggesting that the presence of PNI implies tumor biology aggressiveness.