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Smoking cessation improves treatment tolerance, reduces complications, and lowers recurrence and second primary risks in head and neck cancer. The most effective strategy pairs pharmacotherapy with behavioral support. Varenicline, a partial α4β2 nicotinic receptor agonist, demonstrates superior quit rates compared with bupropion or single-form NRT in many settings. Combining varenicline with structured counseling (individual or group), setting a quit date, addressing triggers, and scheduling proactive follow-ups enhances adherence and relapse prevention. E-cigarettes (Option C) are not first-line due to variable nicotine delivery and uncertain long-term safety; they may be considered harm reduction in select cases when approved therapies fail. Brief advice or PRN gum alone (Options A/D) yields lower sustained quit rates than combination approaches. APRNs should assess neuropsychiatric history, discuss common adverse effects (nausea, vivid dreams), consider combination NRT if varenicline is contraindicated or not tolerated, and integrate cessation plans into oncology pathways, leveraging institutional programs and quitlines for ongoing support.